Pyrazolyl derivatives, preparation process and intermediates of this process as medicinal products and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to the novel derivatives of formula (I) in which 
     
       
         
         
             
             
         
       
     
     A is, if it is present, a (C1-C6) alkyl, a (C3-C6) alkenyl, a (C3-C6) alkynyl, a (C3-C7) cycloalkyl or a (C5-C7) cycloalkenyl, R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group; A-R1 is such that the nitrogen of R1 and the nitrogen in the 1-position of the pyrazole are necessarily separated by at least two carbon atoms, R3 is an H, halogen, OH, SH, NH 2 , ORc, SRc, SORa, SO 2 Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO 2 Ra, R4 is an aryl or heteroaryl; and R5 is an H, halogen, CF 3 , CHF 2 , CH 2 F, linear or branched (C1-C6) alkyl or (C3-C7) cycloalkyl, to their racemates, enantiomers and diastereoisomers and to their mixtures, their tautomers and to their pharmaceutically acceptable salts.

This application claims the benefit of U.S. Provisional Application No.60/537,046 filed Jan. 16, 2004 and benefit of priority from FrenchApplication No. 03 13775, filed Nov. 25, 2003, both of which areincorporated herein by reference in their entirety.

The present invention relates to novel ligands for acetylcholinereceptors of the nicotinic type. These compounds are more particularlyligands for α7 nicotinic receptors. These properties suggest that thecompounds of the invention may be useful, in animals including humans,as a curative and/or symptomatic treatment for the prevention, diagnosisand/or monitoring of the evolution of disorders or diseases whichinvolve a disturbance of nicotinic receptor function or which respondfavorably to a modulation of said receptors. More particularly, thecompounds of the invention could be useful in psychiatric disorders ordiseases or neurological disorders or diseases of the central nervoussystem involving the impairment of cognitive functions, of attention, ofthe ability to concentrate, to learn and to memorize, or of theprocessing of sensory information. They may also be useful in thetreatment, prevention, diagnosis and/or monitoring of the evolution ofdiseases involving neurodegenerative processes which are spontaneous orwhich are subsequent to lesions, and of diseases involving inflammatoryphenomena. The present invention also refers to the methods of treatmentinvolving nicotinic receptors consisting of the administration, toanimals including humans, of therapeutically effective doses of one ormore compounds of the invention. The present invention also relates tothe use, for diagnostic purposes, of analogs of these derivatives inwhich one or more atoms have been replaced with an isotope with anatomic mass or a mass number which is different to the atomic mass or tothe mass number of the atoms usually encountered naturally.

A subject of the present invention is therefore the use of pyrazolederivatives of formula (I)

and their pharmaceutically acceptable salts, for preparing medicinalproducts and pharmaceutical compositions, as ligands for α7 nicotinicreceptors.

Many disorders or diseases are associated with a nicotinic receptordysfunction and may thus benefit from a modulation of said receptorsusing the compounds of the invention to correct the symptoms thereofand/or to slow down, stop or reverse the evolution thereof. In thisregard, the compounds of the invention are more particularlyadvantageous in the case of psychiatric disorders or diseases orneurological disorders or diseases of the central nervous system, suchas, for example, an impairment of the ability to learn, to concentrateor to memorize, slight cognitive impairments, senile dementia, vasculardementia, Levy body dementia, Alzheimer's disease, Parkinson's disease,Huntington's chorea, Tourette's syndrome, neuronal degenerationsubsequent to a trauma, to strokes, to ischemia or to brain hypoxia,multisystem atrophy, progressive supranuclear paralysis, amyotrophiclateral sclerosis, peripheral neuropathies, motor disorders such asdyskinesia, tardive dyskinesia, hyperkinesia, dystonia and epilepsy,attention deficit hyperactivity disorders, schizophrenia, depression,manic depressive psychosis, anxiety, phobias, obsessive-compulsivedisorders, post-traumatic stress syndrome, panic attacks, eatingdisorders such as anorexia, bulimia and obesity, or sleep disordersincluding those associated with jetlag. The compounds of the inventionmay be useful for establishing a decrease in the consumption ofaddictive substances, for helping to maintain an abstinence with respectto said substances or for reducing the symptoms of withdrawal therefrom.In the context of the present invention, the term “addictive substance”applies to licit or illicit substances, the consumption of which maygive rise to abuse and/or dependency, such as, for example, nicotine andtobacco products, alcohol, cannabis derivatives, opiates, cocaine,barbiturates, benzodiazepines and pyschostimulants.

The compounds of the invention could also have an advantage in thetreatment of acute or chronic pain, such as post-surgical pain, painsubsequent to amputation (phantom limb pain), pain associated withcancerous lesions, with migraines, with neuropathies and muscle painssuch as fibromyalgia. In addition, the compounds of the invention couldalso be used in the context of the treatment of disorders or diseasesinvolving inflammatory processes, such as, for example, in thegastrointestinal tract, ulcerative colitis, Crohn's disease, irritablebowel syndrome or diarrhea and, elsewhere in the body, arthritis(including rheumatoid arthritis) and skin inflammations such as acne.Finally, the compounds of the invention could be useful in endocrinedisorders such as pheochromocytoma and smooth muscle contraction-relateddisorders.

The present invention also covers the use of the compounds of theinvention for diagnostic purposes or for the purposes of medicalimaging. It comprises the diagnostic and imaging methods consisting ofthe analysis, by noninvasive methods, of the distribution of a tracercompound within the intact body of an animal, including humans, usingphysical means such as positon emission tomography, single-photontomography, magnetic resonance spectroscopy and nuclear magneticresonance imaging, computed X-ray tomodensitometry (scanner) or acombination of these techniques. In the context of the presentinvention, the term “tracer compound” denotes the compounds of theinvention, their enantiomers or their prodrugs which may or may not beused in a labeled form allowing them to be detected by physical means asdescribed above. The labeling consists in replacing one or more atoms inthe compounds of the invention with an isotope with an atomic mass or amass number which is different to the atomic mass or to the mass numberof these atoms such as they are usually encountered naturally. It mayalso consist in adding to the compounds of the invention chemical groupscarrying such isotopes, by means, for example, of methylating reagents.The isotopes used may, for example, be radionuclide isotopes ofhydrogen, of carbon, of nitrogen, of oxygen, of fluorine, of phosphorus,of sulfur, of chlorine, of iodine or of technetium, such as,respectively, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³ N, ¹⁵O, ¹⁷O, ¹⁸F, ³⁵S, ³⁶Cl,¹²³I, ¹²⁵I and ¹³¹I. The labeled compounds can be synthesized accordingto the methods described in the procedures of the present invention bysubstituting one or more reagents in the synthetic process withidentical reagents containing the label isotope(s).

The present invention relates to derivatives of formula (I) in which:

-   -   A is a bond or (C1-C6) alkyl radical, a (C3-C6) alkenyl radical,        a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical or a        (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an H, halogen, OH, SH, NH₂, ORc, SRc, SORa, SO₂Ra, NHCHO,        NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO₂Ra radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is an H, halogen, CF₃, CHF₂, CH₂F, linear or branched (C1-C6)        alkyl or (C3-C7) cycloalkyl radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, (C4-C7)heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl (C4-C7)heterocycloalkyl,        (hetero)arylalkyl, (hetero)aryl, (poly)-fluoroalkyl, C(O)R8,        C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or the racemates, enantiomers or diastereoisomers or mixtures in        any combination thereof, the tautomers or the pharmaceutically        acceptable salts thereof, with the exception of        3-(3-pyridinyl)-1H-pyrazole-1-butanamine,        4-(3-pyridinyl)-1H-pyrazole-1-butanamine and        N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

Preferably, the present invention relates to derivatives of formula (I)in which:

-   -   A is a bond, a (C1-C6) alkyl radical, a (C3-C6) alkenyl radical,        a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical or a        (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen or Me radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof, with the exception of        3-(3-pyridinyl)-1H-pyrazole-1-butanamine,        4-(3-pyridinyl)-1H-pyrazole-1-butanamine and        N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

More particularly, the present invention relates to derivatives offormula (I) in which:

-   -   A is a bond or (C1-C6) alkyl radical, a (C3-C6) alkenyl radical,        a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical or a        (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof, with the exception of        3-(3-pyridinyl)-1H-pyrazole-1-butanamine,        4-(3-pyridinyl)-1H-pyrazole-1-butanamine and        N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.

In the definitions above and those which follow, the (C1-C6) alkylradicals contain 1 to 6 carbon atoms in a straight or branched chain;the (C3-C7) cycloalkyl radicals contain 3 to 7 carbon atoms; the alkenylradicals contain 2 to 6 carbon atoms and one to 2 conjugated orunconjugated double bonds in a straight or branched chain, the doublebond not being in the alpha-position with respect to a hetero atom; thealkynyl radicals contain 2 to 6 carbon atoms and one to 2 conjugated orunconjugated triple bonds in a straight or branched chain, the triplebond not being in the alpha-position with respect to a hetero atom; thearyl radicals are chosen from phenyl, naphthyl or indenyl; theheteroaryl radicals contain 3 to 10 ring members, optionally containingone or more hetero atoms chosen from oxygen, sulfur and nitrogen, inparticular thiazolyl, thienyl, pyrrolyl, pyrazolyl, pyridinyl, furyl,imidazolyl, oxazolyl, pyrazinyl, pyrimidyl, tetrazolyl, oxadiazolyl,thiadiazolyl, isoxadiazolyl, isothiadiazolyl, isothiazolyl, isoxazolyl,triazolyl, indolyl, benzofuranyl, benzothienyl, azaindolyl, pyrazolyl,indolyl; the halogen radical is either chlorine, iodine, fluorine orbromine; the (C4-C7) azacycloalkyl radicals contain a nitrogen and 4 to7 carbon atoms and in particular azetidinyl, pyrrolidinyl, piperidinyl;the azacycloalkenyl radicals contain a nitrogen and 5 to 7 carbon atoms;the (C5-C9) azabicycloalkyl radicals contain 5 to 9 carbon atoms and areillustrated in a nonlimiting manner in list (A); the (C5-C9)azabicycloalkenyl radicals contain 5 to 9 carbon atoms and areillustrated in a nonlimiting manner in list (B); the (C4-C7)heterocycloalkyl radicals contain 5 to 7 carbon atoms and one or morehetero atoms chosen from oxygen, sulfur and nitrogen; thepolyfluoroalkyl radicals contain 1 to 6 carbon atoms in a straight orbranched chain, which are substituted with one or more fluorine atomsand in particular trifluoromethyl, difluoromethyl;

By way of illustration, below are structures of list (A); thesestructures may be linked to the main ring via any of their positions:

By way of illustration, below are structures of list (B); thesestructures may be linked to the main ring via any of their positions:

The compounds of formula (I) exhibit one or more asymmetric carbons andcan therefore be in the form of isomers, of racemates, of enantiomersand of diastereoisomers; these are also part of the invention as aremixtures thereof.

The present invention also relates to the pharmaceutical compositionscontaining as active principle a derivative of formula (I) in which:

-   -   A is a bond or (C1-C6) alkyl radical, a (C3-C6) alkenyl radical,        a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical or a        (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an H, halogen, OH, SH, NH₂, ORc, SRc, SORa, SO₂Ra, NHCHO,        NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO₂Ra radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is an H, halogen, CF₃, CHF₂, CH₂F, linear or branched (C1-C6)        alkyl or (C3-C7) cycloalkyl radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof.

Preferably, the present invention also relates to pharmaceuticalcompositions containing as active principle a derivative of formula (I)in which:

-   -   A is a bond, a (C1-C6) alkyl radical, a (C3-C6) alkenyl radical,        a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical or a        (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen or Me radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)-arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof.

More particularly, the present invention also relates to thepharmaceutical compositions containing as active principle a derivativeof formula (I) in which:

-   -   A is a bond, or (C1-C6) alkyl radical, a (C3-C6) alkenyl        radical, a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical        or a (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof.

The present invention also relates to the use as a medicinal product ofthe pyrazole derivatives of formula (I) in which:

-   -   A is a bond, or (C1-C6) alkyl radical, a (C3-C6) alkenyl        radical, a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical        or a (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an H, halogen, OH, SH, NH₂, ORc, SRc, SORa, SO₂Ra, NHCHO,        NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO₂Ra radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is an H, halogen, CF₃, CHF₂, CH₂F, linear or branched (C1-C6)        alkyl or (C3-C7) cycloalkyl radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)-arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof.

Preferably, the present invention relates to the use as medicinalproduct of the pyrazole derivatives of formula (I) in which:

-   -   A is a bond, or (C1-C6) alkyl radical, a (C3-C6) alkenyl        radical, a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical        or a (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,        R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen or Me radical,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof.

More particularly, the present invention relates to the use as amedicinal product of pyrazole derivatives of formula (I) in which:

-   -   A is a bond, or (C1-C6) alkyl radical, a (C3-C6) alkenyl        radical, a (C3-C6) alkynyl radical, a (C3-C7) cycloalkyl radical        or a (C5-C7) cycloalkenyl radical; these radicals are optionally        substituted with one or more substituents chosen from (C1-C5)        alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, arylalkyl, heteroarylalkyl, aryl,        heteroaryl and halogen,    -   R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl,        (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group;        these groups are optionally substituted with one or more        substituents chosen from (C1-C5) alkyl, (C3-C5) cycloalkyl and        halogen,    -   A-R1 is such that the nitrogen of R1 and the nitrogen in the        1-position of the pyrazole are necessarily separated by at least        two carbon atoms,    -   R3 is an OH, NH₂, OMe or H radical,    -   R4 is an aryl or heteroaryl radical being optionally substituted        with one or more substituents chosen from halogen, CN, NO₂, NH₂,        OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO,        C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb,        ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra,        NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)        heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,        trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6)        alkenyl and (C2-C6) alkynyl, these substituents being optionally        substituted with one or more alkyl, halogen, OH, methoxy,    -   R5 is a hydrogen,    -   Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,        (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)        heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl        or polyfluoroalkyl,    -   Rb is, independently of Ra, a hydrogen, linear or branched        (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)        cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl,    -   Ra and Rb may form a saturated or unsaturated ring containing 5,        6 or 7 ring members, which may or may not have a hetero atom        such as O, S or N, this ring being optionally substituted with        one or more alkyl and/or halogen radicals,    -   Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl,        (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl,        (C4-C7) heterocycloalkyl, (hetero)arylalkyl, (hetero)aryl,        (poly)fluoroalkyl, C(O)R8, C(S)R8 or SO₂R8 radical,    -   R6 and R7 are, independently of one another, a hydrogen, (C1-C6)        alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,        (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or        heteroarylalkyl,    -   R6 and R7 may form a saturated or unsaturated ring with 5, 6 or        7 ring members, which may or may not have a hetero atom such as        O, S or N and which is optionally substituted with one or more        alkyls and/or halogens,    -   R8 is an Ra or NRaRb radical,        or a racemate, an enantiomer or a diastereoisomer, or a mixture        in any combination thereof, a tautomer or a pharmaceutically        acceptable salt thereof,

Among the compounds of formula (I) which are useful according to theinvention, mention may be made of the following compounds:

-   1-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol-   3-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane-   3-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol-   1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-Dimethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[3-Dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[2-Diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol-   1-(2-Diisopropylaminoethyl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol-   3-(3-Methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo-[2.2.2]octane-   1-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]-piperidine-   4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine-   4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine-   N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]acetamide-   N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]methanesulfonamide-   1-(2-Dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-ol-   1-(1-Methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol-   N-{3-[3-Hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamide-   4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol-   1-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-3-yl)-1H-pyrazol-3-ol-   4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol-   1-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-4-yl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-ol-   4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-Phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol-   3-(4-Phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]-octane-   4-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-3-ol-   4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-pyrazol-3-ol-   1-(1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-[2-(1-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-(Pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-[(1-Methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-[2-(4-Phenylpyrazol-1-yl)ethyl]piperidine-   1-[2-(4-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   3-(3-Difluoromethoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane-   3-(4-Phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane-   4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-Phenyl-1-piperidin-3-yl-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-p-tolyl-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   (S)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol-   (R)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-thiophen-2-yl-1H-pyrazol-3-ol-   4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   1-[(S)-1-(1-Azabicyclo[2.2.2]oct-3-yl)methyl]-4-phenyl-1H-pyrazol-3-ol-   1-[(R)-1-(1-Azabicyclo[2.2.2]oct-3-yl)methyl]-4-phenyl-1H-pyrazol-3-ol-   1-[(1S,4R)-2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-[(1R,4S)-2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-((R)-1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   1-((S)-1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-((R)-1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-[1-(7-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.1]hept-3-yl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-piperidin-2-ylmethyl-1H-pyrazol-3-ol-   1-(1-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   1-(1-Ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   1-(1-Methyl-2-piperidin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)-1-methylethyl]-4-phenyl-1H-pyrazol-3-ol-   1-(2-Dimethylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol-   1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-chlorophenyl)-1H-pyrazol-3-ol-   1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-chlorophenyl)-1H-pyrazol-3-ol-   1-(R)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-fluorophenyl)-1H-pyrazol-3-ol-   1-(S)-1-Azabicyclo[2.2.2]oct-3-yl-4-(3-fluorophenyl)-1H-pyrazol-3-ol-   4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(5-Phenylthiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-(5-pyridin-2-ylthiophen-2-yl)-1H-pyrazol-3-ol-   4-(4-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-ol-   4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3,5-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(6-Chloropyridin-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(1H-Indol-6-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(1H-Indol-3-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(1-Methyl-1H-indol-3-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   N-{4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}methanesulfonamide-   N-{3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}methanesulfonamide-   4-[3-(1H-Imidazol-2-yl)phenyl]-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-[4-(1H-Imidazol-2-yl)phenyl]-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3-Chloro-4-hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Hydroxy-3-methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Amino-3-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-chlorophenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-fluorophenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-hydroxyphenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-hydroxyphenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-chlorophenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-fluorophenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-hydroxyphenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-hydroxyphenyl)-1H-pyrazol-3-ol-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-hydroxyphenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-hydroxyphenyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol-   2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   N-Methyl-2-[1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]-benzamide-   2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzenesulfonamide-   N-Methyl-2-[1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzenesulfonamide-   {2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]phenyl}-methanol-   4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole-3-thiol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine-   N-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-yl]methanesulfonamide-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazole-3-thiol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-phenol-   3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo-[2.2.2]octane-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]phenol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-2-chlorophenol-   3-(3-Cyclopropylmethoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane-   3-[4-(4-Chlorophenyl)-3-cyclopropylmethoxypyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-cyclopropylmethoxy-1H-pyrazol-4-yl]phenol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-cyclopropylmethoxy-1H-pyrazol-4-yl]-2-chlorophenol-   3-[4-Phenyl-3-(2,2,2-trifluoroethoxy)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane-   3-[4-(4-Chlorophenyl)-3-(2,2,2-trifluoroethoxy)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl]phenol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl]-2-chlorophenol-   N-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-3-yl]methanesulfonamide-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazole-3-thiol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ylamine-   2-[2-(4-Phenylpyrazol-1-yl)ethyl]-2-azabicyclo-[2.2.1]heptane-   2-{2-[4-(4-Chlorophenyl)pyrazol-1-yl]ethyl}-2-azabicyclo[2.2.1]heptane-   4-{1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-1H-pyrazol-4-yl}phenol-   4-{1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-1H-pyrazol-4-yl}-2-chlorophenol-   1-[2-(2-Ethyl-4-methylpyrrolidin-1-yl)ethyl]-4-phenyl-1H-pyrazole-3-thiol-   N-{1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-yl}methanesulfonamide-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ylamine-   4-(4-Chlorophenyl)-1-[2-(2-ethyl-4-methylpyrrolidin-1-yl)ethyl]-1H-pyrazole-3-thiol-   N-[1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazol-3-yl]methanesulfonamide-   1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-(4-chlorophenyl)-1H-pyrazol-3-ylamine-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazole-3-thiol-   N-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-yl]methanesulfonamide-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-ylamine-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazole-3-thiol-   1-(1-Methylperhydroazepin-3-yl)-4-phenyl-1H-pyrazol-3-ol-   1-(2-Methylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol-   1-(3-Dimethylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol-   1-(3-Methylaminocyclopentyl)-4-phenyl-1H-pyrazol-3-ol-   1-(2-Dimethylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol-   1-(2-Methylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol-   1-(3-Dimethylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol-   1-(3-Methylaminocyclohexyl)-4-phenyl-1H-pyrazol-3-ol-   1-(Octahydroindolizin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   1-((S)-1-Ethylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-ol-   1-((2R) 1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol-   1-(1-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   1-(1-Methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol-   4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole-   4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole-   4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole-   (+)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole-   (−)-1-(Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-ol-   1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol-   3-[4-(3,5-Difluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octane-   4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol-   1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-ol-   4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ol-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol-   1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-ol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-ol-   3-[4-(4-Chlorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octane-   3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane-   3-[4-(3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane-   4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-2-chlorophenol-   4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol-   (−)-4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol-   (+)-4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine-   (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole-   (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazole,    their racemates, enantiomers and diastereoisomers and their    mixtures, their tautomers and their pharmaceutically acceptable    salt.

The methods of obtaining the derivatives of the present invention areillustrated below and, in order for it to be easier to read theprocesses, the compounds of formula (I) are divided up into eightsubfamilies (Ia) for R3=OH, (Ib) for R3=ORc, (Ic) for R3=H, (Id) forR3=NH₂, (Ie) for R3=NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra, NHSO₂Ra, (If) forR3=SH, (Ig) for R3=SRc, and (Ih) for R3=S(O)Ra, SO₂Ra. The definitionsof various substituents are the same as those of formula (I), unlessotherwise indicated.

For easy reading, groups GP, GP′, GP″, GP′″, GP^(iv) and GP^(v) aregroups which protect functions sensitive to the reaction conditions andare introduced as defined in T. W. Greene et al., Protective Groups inOrganic Synthesis, Wiley-Interscience, third edition (1999), capable ofbeing unaffected by the subsequent steps of the synthesis and of beingdeprotected under conditions which do not affect the rest of themolecule.

The derivatives of formula (I) for which R3 is a hydroxyl (Ia) can beobtained from derivatives of formula (II) (I with R3=OGP) for which GPis a hydroxyl function-protecting group.

The term “GP” is intended to mean a hydroxyl function-protecting group,as defined in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999), capable of beingunaffected by the subsequent steps of the synthesis and of beingdeprotected under conditions which do not affect the rest of themolecule. For example, the GP group may be a silyl-containing group suchas tert-butyldimethylsilyl, triisopropylsilyl or diphenylmethylsilyl, oran alkyl, aralkyl, alkylidene, cycloalkylidene, heteroalkyl orheterocycloalkyl residue such as methyl, allyl, cyclohex-2-enyl, benzylor tetrahydropyran-2-yl. The GP group is preferably a benzyl or acyclohex-2-enyl. The deprotection of the GP group is carried outaccording to the methods described in T. W. Greene et al., ProtectiveGroups in Organic Synthesis, Wiley-Interscience, third edition (1999).

For example, when the GP group is a benzyl, the deprotection is carriedout by hydrolysis in the presence of concentrated hydrochloric acid inan alcohol such as ethanol, methanol or isopropanol at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium,preferably in ethanol, at the boiling temperature of the reactionmedium.

Alternatively, the debenzylation can be carried out by the followingsuccessive operations:

a) Formation of the hydrochloride of the compound to be deprotected inthe presence of hydrochloric acid in aqueous solution or in solution inan organic solvent such as ethanol, methanol, dioxane or diethyl ether,at a temperature in the region of 20° C.;

b) Hydrogenation in the presence of a catalyst such aspalladium-on-charcoal, in an alcohol such as ethanol, methanol orisopropanol, at a hydrogen pressure of between 1 bar and 20 bar and at atemperature of between 20° C. and the boiling temperature of thereaction medium.

The hydrogenolysis of the benzyl group can also be carried out in thepresence of a catalyst such as palladium-on-charcoal, in the presence ofconcentrated hydrochloric acid, in an alcohol such as ethanol, methanolor isopropanol, at a hydrogen pressure of between 1 bar and 30 bar andat a temperature of between 20° C. and the boiling temperature of thereaction medium. The reaction can also be carried out with ammoniumformate, in the presence of a catalyst such as palladium-on-charcoal, inan alcohol such as ethanol, methanol or isopropanol, at a temperaturebetween 20° C. and the boiling temperature of the reaction medium,preferably in methanol at the boiling temperature of the reactionmedium.

When the GP group is a cyclohexenyl, the deprotection is carried out byhydrolysis in acid medium, for example in the presence of a solution ofhydrochloric acid in an ether or an alcohol, in a solvent such asmethanol or ethanol at a temperature of between 20° C. and the boilingtemperature of the reaction medium.

The derivatives of formula I for which R3 is ORc (Rc being different toC(O)R8, C(S)R8, SO₂R8), H, NH₂ or OGP (Ib), (Ic), (Id) or (II) can beobtained according to three different synthetic pathways.

The first synthetic pathway consists in using compounds of formula(III):

The compounds of formula (Ib), (Ic), (Id) or (II) can be obtained from apyrazole of formula (III) and a compound of formula (IV) R1-A-X forwhich X=a function such as Cl, Br, I, OTs, OMs or OTf. The alkylation iscarried out under an inert atmosphere, for example under argon or undernitrogen, in basic medium in an aprotic solvent, for example in thepresence of sodium hydride, in an aprotic solvent such asdimethylformamide, at a temperature of between 20° C. and the boilingtemperature of the reaction medium, or in the presence of potassiumtert-butoxide, in a solvent such as dimethylformamide, at a temperatureof between 20° C. and the boiling temperature of the reaction medium.The reaction can also be carried out in the presence of potassiumcarbonate and, optionally, of potassium iodide, in a solvent such asacetone, methyl ethyl ketone, acetonitrile or dimethylformamide,preferably in methyl ethyl ketone, at the boiling temperature of thereaction medium.

The compounds (IV) are commercial or can be obtained from thecorresponding alcohols of formula R1-A-OH by methods known to thoseskilled in the art such as those described in J. March, Advanced OrganicChemistry, Wiley-Interscience, fourth edition (1992) or R. C. Larock,Comprehensive Organic Transformations, VCH Publishers (1989). Thealcohols of formula R1-A-OH are commercial or can be obtained byadapting methods described in the literature using the basic generalknowledge of those skilled in the art.

The second synthetic pathway can be used for the compounds of formula(I) for which R3 is ORc (Rc being different to C(O)R8, C(S)R8, SO₂R8), Hor OGP, and R1-A is a group in which the radical A is connected to R1 bya nitrogen atom.

The compounds of formula (Ib), (Ic) or (II) can be obtained in three orfour steps from the pyrazoles of formula (III) according to thefollowing protocol:

a) Alkylation of the pyrazole (III) with a compound of formula (V)GP′O-A-X in which GP′ is a hydroxyl function-protecting group, asdefined in T. W. Greene and al., Protective Groups in Organic Synthesis,Wiley-Interscience, third edition (1999), capable of being unalteredduring the alkylation step and of being deprotected under conditionswhich do not affect the rest of the molecule (for example, the GP′ groupmay be a silyl-containing group such as tert-butyldimethylsilyl,triisopropylsilyl or diphenylmethylsilyl, or an aralkyl, alkylidene,cycloalkylidene, heteroalkyl, or heterocycloalkyl residue such as allyl,cyclohex-2-enyl, benzyl or tetrahydropyran-2-yl); the GP′ group ispreferably a tetrahydropyran-2-yl or tert-butyldimethylsilyl group; theradical X is a function such as Cl, Br, I, OTs, OMs or OTf. Thealkylation is carried out under an inert atmosphere, for example underargon or under nitrogen, in basic medium in an aprotic solvent, forexample in the presence of sodium hydride, in an aprotic solvent such asdimethylformamide, at a temperature of between 20° C. and the boilingtemperature of the reaction medium, or in the presence of potassiumtert-butoxide, in a solvent such as dimethylformamide, at a temperatureof between 20° C. and the boiling temperature of the reaction medium.The reaction may also be carried out in the presence of potassiumcarbonate and, optionally, of potassium iodide, in a solvent such asacetone, methyl ethyl ketone, acetonitrile or dimethylformamide,preferably in methyl ethyl ketone, at the boiling temperature of thereaction medium.

b) Production of the intermediates of formula (VI) after cleavage of theGP′ protective group according to the methods described in T. W. Greeneand al., Protective Groups in Organic Synthesis, Wiley-Interscience,third edition (1999), and not affecting the other functions carried bythe molecule. For example, when the GP′ group is a tetrahydropyran-2-yl,the deprotection of the alcohol may be carried out in acid medium, forexample in the presence of aqueous hydrochloric acid, in a solvent suchas ethanol or methanol, at a temperature of between 20° C. and theboiling temperature of the reaction medium, preferably in the presenceof aqueous hydrochloric acid, in ethanol, at a temperature in the regionof 20° C.

a′) Alternatively, when A is an ethyl or (C5-C7) cycloalkyl radical,these radicals being optionally substituted with one or moresubstituents chosen from (C1-C5) alkyl, (C3-C7) cycloalkyl, arylalkyl,heteroarylalkyl, aryl and heteroaryl, the intermediates of formula (VI)can be obtained by reaction between a compound of formula (III) and asuitable epoxide in the presence of a base such as potassiumtert-butoxide, in an aprotic solvent such as dimethylformamide, at atemperature between 20° C. and the boiling temperature of the reactionmedium, according to J. M. Villalgordo, Synthesis 1999, 1613.

c) Activation of the alcohol residue of the compounds of formula (VI),for example by formation of a tosylate or of a mesylate designated “Act”in the synthesis scheme. The reaction is then carried out with tosylchloride or mesyl chloride in basic medium, for example in the presenceof pyridine, in a solvent such as dichloromethane, at a temperature ofbetween −20° C. and the boiling temperature of the reaction medium,preferably at a temperature of between −10° C. and a temperature in theregion of 20° C.

d) Substitution of the activated alcohol residue with a primary orsecondary amine of formula R1H. The reaction is carried out in basicmedium, for example in the presence of potassium carbonate, in a polarsolvent, such as dimethylformamide or acetonitrile, at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium,preferably in dimethylformamide, at a temperature in the region of 80°C.

The compounds (V) are commercial or can be obtained from thecorresponding alcohols of formula GP′O-A-OH by methods known to thoseskilled in the art as described in J. March, Advanced Organic Chemistry,Wiley-Interscience, fourth edition (1992) or R. C. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989). The alcohols of formulaGP′O-A-OH are commercial or can be obtained, for example, bymonoprotection of a dialcohol of formula HO-A-OH according to methodsknown to those skilled in the art as described in J. March, AdvancedOrganic Chemistry, Wiley-Interscience, fourth edition (1992) or R. C.Larock, Comprehensive Organic Transformations, VCH Publishers (1989).The compounds of formula HO-A-OH are commercial or available to thoseskilled in the art using or adapting methods described in theliterature.

A third synthetic pathway consists, when R3 is ORc (Rc being differentto C(O)R8, C(S)R8, SO₂R8), H or OGP, in carrying out the synthesis froma derivative of formula (VII) according to the synthesis schemedescribed below.

The compounds of formula (Ib), (Ic), and (II) can be obtained in twosteps from the compounds of formula (VII) for which Y=Br, I or Cl(preferably Br or I):

a) Alkylation of the 4-halopyrazole of formula (VII) with a compound offormula (IV) as defined above. The reaction is carried out under aninert atmosphere, for example under argon or under nitrogen, in basicmedium in an aprotic solvent, for example in the presence of sodiumhydride, in an aprotic solvent such as dimethylformamide, at atemperature of between 20° C. and the boiling temperature of thereaction medium, or in the presence of potassium tert-butoxide, in asolvent such as dimethylformamide, at a temperature of between 20° C.and the boiling temperature of the reaction medium. The reaction canalso be carried out in the presence of potassium carbonate and,optionally, in the presence of potassium iodide, in a solvent such asacetone, methyl ethyl ketone, acetonitrile or dimethylformamide,preferably in methyl ethyl ketone, at the boiling temperature of thereaction medium.

b) Suzuki coupling of the intermediate obtained and of a boronic acid,of an alkyl or cycloalkyl boronate or of a (hetero)aryldialkyl boron offormula (VIII) for which Rx is an alkyl or cycloalkyl radical. Thereaction is carried out under an inert atmosphere in the presence of aninorganic base such as K₃PO₄, Na₂CO₃ or Ba(OH)₂, and of a palladium salt(catalyst) such as dichlorobis(triphenylphosphine)palladium(PdCl₂(PPh₃)₂), tetrakis(triphenylphosphine)palladium (Pd (PPh₃)₄) or(diphenylphosphino)ferrocenyl palladium (PdCl₂dppf), in a solvent suchas dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane,toluene, xylene or ethanol, optionally in the presence of water, at atemperature of between 20° C. and the boiling temperature of thereaction medium (Kotha S. et al., Tetrahedron 2002, 58, 9633).

The boronic acids, alkyl or cycloalkyl boronates or (hetero)aryldialkylboron of formula (VIII) are commercial or are obtained using or adaptingmethods described in the literature, for example in G. W. Kabalka etal., Tetrahedron Letters 1986, 27, 3843, J. F. Nicoud et al.,Tetrahedron Letters 1993, 34, 8237, J. M. Tour et al., J. Amer. Chem.Soc. 1994, 116, 11723, or T. J. J. Mueller et al., Synthesis 2002, 9,1163.

The intermediates of formula (III), when there is a radical ORc (Rcbeing different to C(O)R8, C(S)R8, SO₂R8) and OGP in the 3-position ofthe pyrazole, are obtained according to the reaction scheme representedbelow:

The pyrazoles of formula (III) can be obtained in four steps from thecompounds of formula (IX) according to the following protocol:

a) Condensation of an (aryl)alkyl (hetero)aryl acetate for whichRx=alkyl or aralkyl, of formula (IX), with an aminomethylenation agentor a carbonylation agent of formula (X) for which Ry is a Cl, O-alkyl,O-aralkyl or O—CO-alkyl radical, preferably for which Ry is an O-alkylradical. The aminomethylenation reaction can be carried out in thepresence of a reagent such as N,N,N′,N′,N″,N″-hexamethylmethanetriamine,C-methoxy-N,N,N′,N′-tetramethylmethanediamine orC-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine, in the absence ofsolvent or in a solvent such as tetrahydrofuran or dioxane at atemperature of between 20° C. and the boiling temperature of thereaction medium, preferably in the presence ofC-tert-butoxy-N,N,N′,N′-tetramethyl-methanediamine in tetrahydrofuran ata temperature of between 20° C. and the boiling temperature of thereaction medium. The carbonylation reaction between an (aryl)alkyl(hetero)aryl acetate and a carbonylation agent of formula (X) is carriedout under an inert atmosphere, for example under argon or undernitrogen, in basic medium, for example in the presence of sodiumhydride, in an aprotic solvent such as dimethylformamide, at atemperature of between −20° C. and the boiling temperature of thesolvent, preferably at a temperature in the region of 20° C.

b) Formation of the 1H-pyrazol-3-ol ring by reaction of the intermediateobtained in the preceding step with hydrazine, generally in monohydrateform, in an alcohol such as ethanol, propanol or isopropanol, at atemperature of between 20° C. and the boiling temperature of thereaction medium, preferably in ethanol, at the boiling temperature ofthe reaction medium.

c) Protection of the nitrogen in the 1-position of the 1H-pyrazol-3-olwith a protective group such as an acetyl, alkyloxycarbonyl or tosyl,preferably with an acetyl group. The reaction is carried out with anacetylating, alkyloxycarbonylating or tosylating agent, preferably withacetic anhydride without solvent or in the presence of a solvent such aspyridine, at a temperature of between 20° C. and the boiling temperatureof the reaction medium, preferably at a temperature in the region of100° C.

d) Protection of the hydroxyl group of the pyrazole or introduction ofthe −Rc residue onto the hydroxyl of the pyrazole, followed bydeprotection of the nitrogen in the 1-position of the pyrazole. Theprotection of the hydroxyl group of the pyrazole and the introduction ofthe −Rc residue onto the hydroxyl of the pyrazole can be carried out,for example, by alkylation of the hydroxyl group of the pyrazole withthe compounds of formula GP-X or Rc-X for which X is a function such asCl, Br, I, OTs, OMs or OTf. When Rc=Me or Et, dimethyl sulfate ordiethyl sulfate can also be used as alkylating agent and will preferablybe chosen. The reaction is carried out in basic medium, for example inthe presence of a base such as potassium carbonate, in a solvent such asacetone, methyl ethyl ketone, acetonitrile or dimethylformamide, at atemperature of between 20° C. and the boiling temperature of thereaction medium, preferably in methyl ethyl ketone, at the boilingtemperature of the reaction medium. When Rc=—CHF₂, the alkylation can becarried out with methyl chlorodifluoroacetate, in basic medium, forexample in the presence of a base such as potassium carbonate, in asolvent such as dimethylformamide, at a temperature of between 20° C.and the boiling temperature of the reaction medium, preferably at atemperature in the region of 65° C. The deprotection of the nitrogen inthe 1-position of the pyrazole is carried out according to the methodsdescribed in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999). For example, whenthe protective group is an acetyl, the deprotection can be carried outin the presence of a base such as sodium hydroxide or potassiumcarbonate, in an alcohol such as ethanol or methanol, to which a solventsuch as tetrahydrofuran or dioxane is optionally added, at a temperatureof between 20° C. and the boiling temperature of the reaction medium,preferably in the presence of sodium hydroxide in a mixture of ethanoland tetrahydrofuran, at a temperature in the region of 20° C.

The compounds of formula (IX) are commercial or can be obtained using oradapting methods described in the literature.

The compounds of formula (X) are commercial or can be obtained using oradapting methods described in the literature.

The compounds of formula GP-X are commercial. The compounds of formulaRc-X are commercial or can be obtained from the corresponding alcoholsof formula Rc-OH by the methods known to those skilled in the art asdescribed in J. March, Advanced Organic Chemistry, Wiley-Interscience,fourth edition (1992) or R. C. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989). The alcohols of formula Rc-OHare commercial or can be obtained using or adapting methods described inthe literature.

The intermediates of formula (III), when there is a hydrogen in the3-position of the pyrazole, are obtained according to the reactionscheme represented below:

The compounds of formula (III) can be obtained from the compounds offormula (XI) or (XII) and hydrazine, generally in monohydrate form. Thereaction is carried out, for example, in an alcohol such as ethanol,propanol or isopropanol, at a temperature in the region of 20° C. andthe boiling temperature of the reaction medium, preferably in ethanol,at the boiling temperature of the reaction medium.

The compounds of formula (XI) or (XII) are commercial or can be obtainedusing or adapting methods described in the literature.

The intermediates of formula (III), when there is a radical ORc (Rcbeing different to C(O)R8, C(S)R8, SO₂R8) or OGP or H in the 3-positionof the pyrazole, can also be obtained according to the reaction schemerepresented below:

The compounds of formula (III) can be prepared in three or four stepsfrom compounds of formula (VII):

a) Protection of the compounds of formula (VII), for example with atosyl, mesyl or acetyl group, preferably with a tosyl group. Thisreaction is carried out according to the processes known to thoseskilled in the art and described in T. W. Greene et al., ProtectiveGroups in Organic Synthesis, Wiley-Interscience, third edition (1999).For example, when the protective group is a tosyl, the reaction iscarried out with tosyl chloride in basic medium, for example in thepresence of sodium hydride or of potassium tert-butoxide in an aproticsolvent such as dimethylformamide at a temperature between −10° C. andthe boiling temperature of the reaction medium.

b) Introduction of the R4 group by Suzuki coupling or by two consecutiveStille reactions. The introduction of the R4 group by Suzuki coupling iscarried out using the protected 4-halopyrazole obtained in the precedingstep and a boronic acid, an alkyl or cycloalkyl boronate or a(hetero)aryldialkyl boron of formula (VIII) for which Rx is an alkyl orcycloalkyl radical, under an inert atmosphere, in the presence of aninorganic base such as K₃PO₄, Na₂CO₃ or Ba(OH)₂, of a palladium salt(catalyst) such as dichlorobis(triphenylphosphine)palladium(PdCl₂(PPh₃)₂), tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) or(diphenylphosphino)ferrocenyl palladium (PdCl₂dppf), in a solvent suchas dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane,toluene, xylene or ethanol, optionally in the presence of water, at atemperature of between 20° C. and the boiling temperature of thereaction medium. Alternatively, the introduction of the R4 group can becarried out with two consecutive Stille reactions. The first Stillereaction is carried out under an inert atmosphere using the protected4-halopyrazole obtained in the preceding step and bis(tributyltin) inthe presence of cuprous iodide, of a palladium salt (catalyst) such aspalladium diacetate (Pd(OAc)₂) and of triphenylphosphine, in a solventsuch as tetrahydrofuran at a temperature of between 20° C. and theboiling temperature of the reaction medium, according to A. I. Scott etal., Tetrahedron Lett. 1996, 37, 3247. The second Stille reaction iscarried out using the organotin above and a halogenated aromaticderivative of formula R4-Z for which Z is a Br, I or Cl radical(preferably Br or I), with a palladium salt (catalyst) such astris(dibenzylidene)dipalladium (Pd2 dba3) and tristrifurylphosphine, ina solvent such as dioxane at a temperature of between 20° C. and theboiling temperature of the reaction medium, according to U. Hacksell etal., Bioorg. & Med. Chem. Lett., 1994, 2837.

c) Cleavage of the protective group introduced in the first step. Thisreaction is carried out according to the processes known to thoseskilled in the art and described in T. W. Greene et al., ProtectiveGroups in Organic Synthesis, Wiley-Interscience, third edition (1999).For example, when the protective group is a tosyl, the reaction can becarried out with tetrabutylammonium fluoride in a solvent such astetrahydrofuran or dioxane at a temperature between 20° C. and theboiling temperature of the reaction medium according to T. Sakamoto etal., Tetrahedron Lett. 1998, 39, 595.

The intermediates (III), when there is an NH₂ radical in the 3-positionof the pyrazole, can be obtained according to the following scheme:

The compounds of formula (III) can be obtained by condensation ofhydrazine, generally in monohydrate form, with a2-(hetero)aryl-3-oxopropionitrile of formula (XIII) in acid medium, forexample in the presence of acetic acid, in an alcohol such as ethanol,propanol or isopropanol, at a temperature of between 20° C. and theboiling temperature of the reaction medium, preferably in ethanol, atthe boiling temperature of the reaction medium.

The compounds of formula (XIII) can be obtained using or adaptingmethods described in the literature.

The intermediates (VII) for which there is an H, OGP or ORc (Rc beingdifferent to C(O)R8, C(S)R8, SO₂R8) in the 3-position of the pyrazoleare obtained from the derivative of formula (XIV)

The intermediates (VII) for which Y=Br, I or Cl (preferably Br or I) arecommercial or can be obtained from intermediates of formula (XIV). Thereaction is carried out with a halogenating agent such as bromine oriodine chloride in a solvent such as dichloromethane or chloroform, inthe presence of a base such as potassium carbonate, at a temperature ofbetween −10° C. and the boiling temperature of the reaction medium,preferably with bromine, in dichloromethane, at a temperature in theregion of 20° C.

The intermediates (XIV) for which there is a hydrogen in the 3-positionof the pyrazole are commercial or are obtained using or adapting themethods described in the literature.

The intermediates (XIV) for which there is an OGP radical or an ORcradical (Rc being different to C(O)R8, C(S)R8, SO₂R8) in the 3-positionof the pyrazole can be obtained in two steps from compounds of formula(XV) according to the following protocol:

a) Protection of the nitrogen in the 1-position of the 1H-pyrazol-3-olwith a protective group such as an acetyl, alkyloxycarbonyl or tosyl,preferably with an acetyl group. The reaction is carried out with anacetylating, alkyloxycarbonylating or tosylating agent, preferably withacetic anhydride without solvent or in the presence of a solvent such aspyridine, at a temperature of between 20° C. and the boiling temperatureof the reaction medium, preferably at a temperature in the region of100° C.

b) Protection of the hydroxyl group of the pyrazole or introduction ofthe −Rc residue onto the hydroxyl of the pyrazole, followed bydeprotection of the nitrogen in the 1-position of the pyrazole. Theprotection of the hydroxyl-group of the pyrazole and the introduction ofthe −Rc residue onto the hydroxyl of the pyrazole can be carried out byalkylation of the hydroxyl group of the pyrazole with the compounds offormula GP-X or Rc-X for which X is a function such as Cl, Br, I, OTs,OMs or OTf. When Rc is a methyl or ethyl group, dimethyl sulfate ordiethyl sulfate can also be used as alkylating agent and will preferablybe chosen. The reaction is carried out in basic medium, for example inthe presence of a base such as potassium carbonate, in a solvent such asacetone, methyl ethyl ketone, acetonitrile or dimethylformamide, at atemperature of between 20° C. and the boiling temperature of thereaction medium, preferably in methyl ethyl ketone, at the boilingtemperature of the reaction medium. When Rc is a CHF₂ group, thealkylation can be carried out with methyl chlorodifluoroacetate, inbasic medium, for example in the presence of a base such as potassiumcarbonate, in a solvent such as dimethylformamide, at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium,preferably at a temperature in the region of 65° C. The deprotection ofthe nitrogen of the pyrazole is carried out according to the methodsdescribed in T. W. Greene et al., in Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999). For example, whenthe protective group is an acetyl, the deprotection can be carried outin the presence of a base such as sodium hydroxide or potassiumcarbonate, in an alcohol such as ethanol or methanol, with a solventsuch as tetrahydrofuran or dioxane being optionally added, at atemperature of between 20° C. and the boiling temperature of thereaction medium, preferably in the presence of sodium hydroxide in amixture of ethanol and tetrahydrofuran, at a temperature in the regionof 20° C.

The compounds of formula (XV) are obtained using or adapting the methodsdescribed in the literature.

The compounds of formula (Id) can also be obtained in seven or eightsteps from the compounds of formula (XVI) for which Y=Br, I or Cl(preferably Br or I), according to the following protocol:

a) Protection of the 4-halo-3-nitropyrazoles of formula (XVI), forexample with a 2-trimethylsilanylethoxymethyl group. This reaction iscarried out according to the processes known to those skilled in the artand described in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999). For example, thereaction is carried out with 2-trimethylsilanylethoxymethyl chloride inbasic medium, for example in the presence of sodium hydride in anaprotic solvent such as dimethylformamide at a temperature of between−10° C. and the boiling temperature of the reaction medium.

b) Introduction of the R4 group by means of Suzuki coupling or by meansof two consecutive Stille reactions. The introduction of the R4 group bymeans of Suzuki coupling is carried out using the protected4-halo-3-nitropyrazole obtained in the preceding step and a boronicacid, an alkyl or cycloalkyl boronate or a (hetero)aryldialkyl boron offormula (VIII) for which Rx is an alkyl or cycloalkyl radical, under aninert atmosphere, in the presence of an inorganic base such as K₃PO₄,Na₂CO₃ or Ba(OH)₂, and of a palladium salt (catalyst) such asdichlorobis(triphenylphosphine)palladium (PdCl₂(PPh₃)₂),tetrakistriphenylphosphine palladium (Pd(PPh₃)₄) ordiphenylphosphinoferroceynyl palladium (PdCl₂dppf), in a solvent such asdimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane, toluene,xylene or ethanol, optionally in the presence of water at a temperatureof between 20° C. and the boiling temperature of the reaction medium.Alternatively, the introduction of the R4 group can be carried out bymeans of two consecutive Stille reactions. The first Stille reaction iscarried out under an inert atmosphere using the protected4-halo-3-nitropyrazole obtained in the preceding step andbis(tributyltin) in the presence of cuprous iodide, of a palladium salt(catalyst) such as palladium diacetate (Pd(OAc)₂) and oftriphenylphosphine, in a solvent such as tetrahydrofuran, at atemperature of between 20° C. and the boiling temperature of thereaction medium, according to A. I. Scott et al., Tetrahedron Lett.1996, 37, 3247. The second Stille reaction is carried out using thepreceding organotin and a halogenated aromatic derivative of formulaR4-Z for which Z is a Br, I or Cl radical (preferably Br or I), with apalladium salt (catalyst) such as tris(dibenzylidene)dipalladium (Pd₂dba₃) and tristrifurylphosphine, in a solvent such as dioxane at atemperature of between 20° C. and the boiling temperature of thereaction medium, according to U. Hacksell et al., Bioorg. & Med. Chem.Lett., 1994, 2837.

e) Reduction of the nitro function according to a protocol as describedin J. March, Advanced Organic Chemistry, Wiley-Interscience, fourthedition (1992) or R. C. Larock, Comprehensive Organic Transformations,VCH Publishers (1989). For example, this reaction can be carried outusing iron in the presence of ammonium chloride in a mixture of analcohol such as ethanol and of water at a temperature of between 20° C.and the boiling temperature of the reaction medium.

f) Double protection of the amino residue obtained in the preceding stepwith a protective group GP^(v). The group GP^(v) is an amine-protectinggroup as defined in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999) and resistant to theconditions for deprotecting the group GP^(iv). For example, the groupGP^(v) may be an allyl, a benzyl or a para-methoxybenzyl. The groupGP^(v) is introduced according to the processes known to those skilledin the art and described in T. W. Greene et al., Protective Groups inOrganic Synthesis, Wiley-Interscience, third edition (1999). Forexample, when the protective group GP^(v) is an allyl, the reaction iscarried out with allyl bromide in the presence of a base such as cesiumcarbonate, in an aprotic solvent such as acetonitrile ordimethylformamide, at a temperature of between 20° C. and the boilingtemperature of the reaction medium.

g) Cleavage of the protective group GP^(iv) introduced in the firststep, according to the processes known to those skilled in the art anddescribed in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999). For example, whenthe protective group GP^(iv) is a 2-trimethylsilanylethoxymethyl, thereaction can be carried out with tetrabutylammonium fluoride in asolvent such as tetrahydrofuran or dioxane, at a temperature of between20° C. and the boiling temperature of the reaction medium.

h) Alkylation of the compound obtained in the preceding step with acompound of formula (IV) R1-A-X, as defined above. The reaction iscarried out under an inert atmosphere, for example under argon or undernitrogen, in basic medium in an aprotic solvent, for example in thepresence of sodium hydride, in an aprotic solvent such asdimethylformamide, at a temperature of between 20° C. and the boilingtemperature of the reaction medium, or in the presence of potassiumtert-butoxide, in a solvent such as dimethylformamide, at a temperatureof between 20° C. and the boiling temperature of the reaction medium.The reaction can also be carried out in the presence of potassiumcarbonate and, optionally, in the presence of potassium iodide, in asolvent such as acetone, methyl ethyl ketone, acetonitrile ordimethylformamide, preferably in methyl ethyl ketone, at the boilingtemperature of the reaction medium.

i) Cleavage of the protective group GP^(v) introduced in step f),according to the processes known to those skilled in the art anddescribed in T. W. Greene et al., Protective Groups in OrganicSynthesis, Wiley-Interscience, third edition (1999). For example, whenthe protective group GP^(v) is an allyl, the reaction can be carried outwith a palladium salt such as tetrakistriphenylphosphine palladium(Pd(PPh₃)₄) in the presence of an acid such as N,N-dimethylbarbituricacid, in an aprotic solvent such as dichloromethane, at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium.

The compounds of formula (XVI) are commercially available or areobtained by analogy with methods described in the literature.

The compounds (Ib) for which Rc is a C(O)R8, C(S)R8 or SO₂R8 radical canbe obtained from the compounds (Ia) according to the protocols known tothose skilled in the art and described, for example, in J. March,Advanced Organic Chemistry, Wiley-Interscience, fourth edition (1992),R. C. Larock, Comprehensive Organic Transformations, VCH Publishers(1989) or Bradford P. Mundy and Michael G. Ellerd, Name Reactions andReagents in Organic Synthesis, A. Wiley-Interscience Publication (1988).

The compounds (Ie) can be obtained from the compounds (Id) according tothe protocols known to those skilled in the art and described, forexample, in J. March, Advanced Organic Chemistry, Wiley-Interscience,fourth edition (1992), R. C. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989) or Bradford P. Mundy and MichaelG. Ellerd, Name Reactions and Reagents in Organic Synthesis, A.Wiley-Interscience Publication (1988).

The compounds (If) can be obtained from the compounds (Ia) by reactionwith a thionating agent, such as, for example, Lawesson's reagent, andaccording to the protocols described, for example, in J. March, AdvancedOrganic Chemistry, Wiley-Interscience, fourth edition (1992).

The compounds (Ig) can be obtained from the compounds (If) according tothe protocols known to those skilled in the art and described, forexample, in J. March, Advanced Organic Chemistry, Wiley-Interscience,fourth edition (1992), R. C. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989) or Bradford P. Mundy and MichaelG. Ellerd, Name Reactions and Reagents in Organic Synthesis, A.Wiley-Interscience Publication (1988).

The compounds (Ih) can be obtained by oxidation of the compounds (Ig)for which Rc=Ra using reagents such as, for example, hydrogen peroxide,potassium permanganate or oxone, and according to the protocolsdescribed, for example, in J. March, Advanced Organic Chemistry,Wiley-Interscience, fourth edition (1992).

The compounds of formula (I) for which the R4 group is substituted withone or more OH radicals can be obtained by demethylation of thecorresponding methoxylated compounds according to a protocol which doesnot affect the rest of the molecule, as described in Protective Groupsin Organic Synthesis, T. W. Greene, Ed. by Wiley, third edition (1999).This reaction can, for example, be carried out with boron tribromide ina solvent such as dichloromethane at a temperature of between −5° C. andthe boiling temperature of the reaction medium.

The compounds of formula (I) for which the R4 group is substituted withone or more NH₂ radicals can be obtained by reduction of thecorresponding nitro compounds according to a protocol as described in J.March, Advanced Organic Chemistry, Wiley-Interscience, fourth edition(1992) or R. C. Larock, Comprehensive Organic Transformations, VCHPublishers (1989). For example, this reaction can be carried out byhydrogenation in the presence of a catalyst such aspalladium-on-charcoal and, optionally, of an acid such as hydrochloricacid, in an alcohol such as ethanol, methanol or isopropanol, at ahydrogen pressure of between 1 bar and 20 bar and at a temperature ofbetween 20° C. and the boiling temperature of the reaction medium.

The compounds of formula (Ib), (Ic) or (II) for which the R4 group issubstituted with one or more NRaRb, NHC(O)Ra, C(O)NRaRb, NHSO₂Ra orNHC(S)Ra radicals can be obtained by reduction of the correspondingnitro compounds, followed by appropriate functionalization of the aminoderivatives obtained. The reduction of the nitro compounds is carriedout according to a protocol which does not affect the rest of themolecule, as described in J. March, Advanced Organic Chemistry,Wiley-Interscience, fourth edition (1992) or R. C. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989). For example, thisreaction can be carried out with a reducing agent such as iron powder,in the presence of ammonium chloride in a mixture of water and of analcohol such as methanol or ethanol, at a temperature between 20° C. andthe boiling temperature of the reaction medium, preferably in ethanol atthe boiling temperature of the reaction medium. The functionalization ofthe resulting amino derivatives is carried out according to methodswhich do not affect the rest of the molecule, known to those skilled inthe art and described, for example, in J. March, Advanced OrganicChemistry, Wiley-Interscience, fourth edition (1992), R. C. Larock,Comprehensive Organic Transformations, VCH Publishers (1989), BradfordP. Mundy and Michael G. Ellerd, Name Reactions and Reagents in OrganicSynthesis, A. Wiley-Interscience Publication (1988) or Hartwig J. F.,Angew. Chem. Int. Ed. Engl. 1998, 2047.

The compounds of formula (Ib), (Ic) or (II) for which the R4 group issubstituted with one or more aryl or heteroaryl radicals can be obtainedfrom the corresponding halogenated compounds (preferably brominated oriodinated) and from suitable boronic acids, alkyl or cycloalkylboronates or (hetero)aryldialkyl borons by Suzuki coupling. Thisreaction is carried out under an inert atmosphere in the presence of aninorganic base such as K₃PO₄, Na₂CO₃ or Ba(OH)₂, of a palladium salt(catalyst) such as dichlorobis(triphenylphosphine)palladium(PdCl₂(PPh₃)₂), tetrakis(triphenylphosphine)palladium (Pd (PPh₃)₄) or(diphenylphosphino)ferrocenyl palladium (PdCl₂dppf), in a solvent suchas dimethylformamide, dimethoxyethane, tetrahydrofuran, dioxane,toluene, xylene or ethanol, optionally in the presence of water, at atemperature of between 20° C. and the boiling temperature of thereaction medium.

The compounds of formula (I) are isolated and can be purified byconventional known methods, for example by crystallization,chromatography or extraction.

The compounds of formula (I) can be optionally transformed into additionsalts with an inorganic or organic acid by reaction of such an acid inan organic solvent such as an alcohol, a ketone or an ether or achlorinated solvent. These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, mention may be made ofthe following salts: benzenesulfonate, hydrobromide, hydrochloride,citrate, ethanesulfonate, fumarate, gluconate, iodate, maleate,isethionate, methanesulfonate, nitrate, oxalate, palmoate, phosphate,salicylate, succinate, sulfate, tartrate, theophylline acetate andp-toluenesulfonate.

The compounds of the invention have been tested with regard to theirability to bind nicotinic receptors containing the α7 subunit by meansof a binding assay on rat brain membrane preparations according to themethods described below:

Membrane Preparations:

Frozen samples of Sprague-Dawley female rat brain hippocampus wereconserved at −20° C. until use. The hippocampi from 10 rats were groupedtogether and homogenized using a Polytron grinder in 10 volumes of abuffer, cooled in ice, having the following composition: KCl (11 mM);KH₂PO₄ (6 mM); NaCl (137 mM); Na₂HPO₄ (8 mM); HEPES (20 mM);iodoacetamide (5 mM); EDTA (1.5 mM); PMSF (0.1 mM). The pH was adjustedto 7.4 using NaOH. The mixture obtained was centrifuged at 24 000 g for20 minutes at 4° C. and the pellet was resuspended in 20 volumes ofice-cold water. After incubation for 60 minutes at 4° C., a furtherpellet was obtained by centrifugation at 24 000 g for 20 minutes at 4°C. The latter was resuspended in buffer having the above composition andfrozen at −20° C. On the day of the assay, the membranes were thawed,centrifuged at 24 000 g for 20 minutes, and then resuspended at a finalconcentration of 2-5 mg of proteins/ml in Dulbecco phosphate buffer atpH 7.4 containing 0.05% of bovine serum albumin.

Measurement of the Affinity for Receptors Containing the α7 Subunit:

The binding of the compounds of the invention to receptors containingthe α7 subunit was measured by competition with respect to[³H]-methyllycaconitine ([³H]-MLA), a radiolabeled tracer whichrecognizes α7 receptors (Davies et al., Neuropharmacology 1999, 38,679-690), according to conventional methods adapted to the 96-well-plateformat. The ability of the compounds of the invention to displace thebinding of [³H]-MLA to rat hippocampal membranes was determined induplicate after incubation for 2 hours at ambient temperature. Each wellcontained a sample of approximately 150 μg of membrane proteins, 5 nM of[³H]-MLA and one of the compounds of the invention diluted to a givenconcentration in Dulbecco phosphate buffer at pH 7.4 containing 0.05% ofbovine serum albumin, for a final volume of 150 μL. The nonspecificbinding was determined in specific wells containing 10 μM ofnon-radiolabeled MLA. The incubation was stopped by filtering thecontent of each well through glass fiber filters (Whatman GF/B)presoaked in a solution of polyethylenimine at 0.33% in Dulbeccophosphate buffer so as to decrease the nonspecific binding. The filterswere then washed 3 times with Dulbecco phosphate buffer, and then driedat 50° C. for approximately 2 hours. The radioactivity retained on thefilters was measured by applying scintillant (MeltiLex A, Perkin Elmer)followed by counting by luminometry (Trilux 1450 microbeta,Perkin-Elmer).

Data Analysis

For each compound tested, the residual radioactivity on the filters wasexpressed in counts per minutes. The determinations in duplicate wereaveraged and the concentration of compound which inhibits by half thespecific binding of the radioactive tracer (IC₅₀) was calculated bycurvilinear regression using specific software (GraphPad Prism). Theapparent affinity constants Ki for the compounds of the invention werecalculated using the Cheng and Prusoff equation (Cheng and Prusoff,Biochem. Pharmacol. 1973, 22, 3099-3108).

The compounds of the invention which were studied in this assay exhibita Ki value of less than 10 μM.

The following examples illustrate the invention in a nonlimiting manner.

EXAMPLE 1 1-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidinedihydrochloride

0.303 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.25 g of 3-methoxy-4-phenylpyrazole in 20 cm³ ofanhydrous dimethylformamide. After stirring for three quarters of anhour at a temperature in the region of 50° C., 0.793 g of1-(2-chloroethyl)piperidine is added in small portions, and the mixtureis then heated for 8 hours at a temperature in the region of 50° C. Themixture is cooled to ambient temperature, 10 cm³ of water are thenadded, and the mixture is concentrated to dryness under reduced pressure(3 kPa). The evaporation residue is taken up in 25 cm³ of water andextracted with 250 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, and is then dried over anhydrous magnesiumsulfate, filtered and concentrated to dryness under reduced pressure (3kPa), so as to give an oily residue which is purified by chromatographyon silica gel (particle size 15-35 μm), eluting with a mixture of ethylacetate and cyclohexane (67/33 by volume). After concentration of thefractions under reduced pressure, 0.3 g of a colorless oil is obtained,which is dissolved in 15 cm³ of acetone and 30 cm³ of an approximately3M solution of hydrochloric ether are added. The white precipitateformed is filtered and then dried under vacuum (70 Pa) at a temperatureof 60° C. 0.325 g of1-[2-(3-methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine dihydrochloride isthus obtained in the form of a white solid which melts at 208° C. (withdecomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.94 (mt: 2H); from 3.40 to 3.60 (mt: 4H); 3.95(s: 3H); 4.47 (t, J=6.5 Hz: 2H); 7.29 (broad t, J=7.5 Hz: 1H); 7.36(broad t, J=7.5 Hz: 2H); 7.62 (broad d, J=7.5 Hz: 2H); 8.14 (s: 1H);10.03 (unresolved peak: 1H).

IR spectrum (KBr): 3031; 2945; 2632; 2540; 1606; 1579; 1518; 1456; 1411;1047; 1030; 764 and 697 cm⁻¹.

The 3-methoxy-4-phenylpyrazole can be prepared in the following way:

A suspension of 2 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, 1.37g of potassium carbonate and 1.13 cm³ (1.5 g) of dimethyl sulfate in 70cm³ of 2-butanone is stirred at a temperature of 70° C. for 4 hours. 24cm³ of a 1.66N sodium hydroxide solution are added to the mixture, whichis stirred for 4 hours at ambient temperature and then partiallyconcentrated under reduced pressure (3 kPa) in order to drive off the2-butanone. The residue is taken up with 10 cm³ of water and extractedwith 250 cm³ of ethyl acetate. The organic phase is washed with 3 times25 cm³ of water, and is then dried over anhydrous magnesium sulfate,filtered and concentrated to dryness under reduced pressure (3 kPa), soas to give a light brown solid residue, which is purified bychromatography on silica gel (particle size 15-35 μm), eluting with amixture of dichloromethane and methanol (98.5/1.5 by volume). Afterconcentration of the fractions under reduced pressure, 0.3 g of3-methoxy-4-phenylpyrazole is obtained in the form of a pale yellowpowder which melts at 150° C.

The 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone can be prepared in thefollowing way:

3.4 cm³ of acetic anhydride are added, over 10 minutes, to a solution of6.4 g of 4-phenyl-1H-pyrazol-3-ol in 64 cm³ of pyridine preheated to100° C. After a further 30 minutes at 100° C., the mixture is cooled andpoured into 600 cm³ of a water-ice mixture. The precipitate whichappears is filtered, washed with 4 times 100 cm³ of ice-water then with4 times 100 cm³ of heptane, and then dried under vacuum (70 Pa) at atemperature of 60° C. 5.09 g of1-(3-hydroxy-4-phenylpyrazol-1-yl)-ethanone are thus obtained in theform of a beige powder which melts at 215° C.

The 4-phenyl-1H-pyrazol-3-ol can be obtained according to the methoddescribed by D. L. Selwood et al., J. Med. Chem. 2001, 44, 78-93.

EXAMPLE 2 1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-oldihydrochloride

A suspension of 0.67 g of3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane and0.08 g of palladium-on-charcoal (10%) in 20 cm³ of ethanol is stirred inan autoclave under a hydrogen pressure of 500 kPa, at a temperature of20° C., for 20 hours. The reaction medium is then filtered over Celite®and concentrated to dryness under reduced pressure (3 kPa), so as togive a pasty residue, which is covered with 50 cm³ of acetone andtriturated overnight. After filtration of the solid which has appearedand drying under vacuum (70 Pa) at a temperature of 60° C., 0.265 g of1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-oldihydrochloride is obtained in the form of hygroscopic beige crystalswhich melt at around 240° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 1.95 (mt:4H); from 1.95 to 2.15 (mt: 1H); from 2.40 to 2.60 (mt: 1H); 2.96 (broaddd, J=12.5 and 7.5 Hz: 1H); from 3.10 to 3.40 (mt: 5H); 4.03 (dd, J=13.5and 7.5 Hz: 1H); 4.10 (dd, J=13.5 and 7.5 Hz: 1H); 7.15 (broad t, J=7.5Hz: 1H); 7.34 (broad t, J=7.5 Hz: 2H); 7.66 (broad d, J=7.5 Hz: 2H);8.00 (s: 1H); 10.51 (unresolved peak: 1H).

IR spectrum (KBr): 3417; 2940; 2546; 1601; 1474; 1388; 1189; 768; 702and 611 cm⁻¹.

EXAMPLE 33-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanedihydrochloride

A solution of 5 g of 3-benzyloxy-4-phenylpyrazole in 30 cm³ of anhydrousdimethylformamide are added gradually, under an argon atmosphere and atambient temperature, to a suspension of 3.84 g of sodium hydride (75% bymass in liquid petroleum jelly) in 20 cm³ of anhydrousdimethylformamide. After stirring for three quarters of an hour at atemperature in the region of 50° C., 11.78 g of3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride are added insmall portions, and the mixture is then heated for 18 hours at atemperature in the region of 50° C. The mixture is cooled to ambienttemperature and 25 cm³ of water are then added slowly, and the mixtureis then run into 300 cm³ of water and extracted with two times 300 cm³of ethyl acetate. The pooled organic phases are washed with 3 times 100cm³ of water, and then dried over anhydrous magnesium sulfate, filteredand concentrated to dryness under reduced pressure (3 kPa). The oilyresidue obtained is purified by chromatography on alumina, eluting witha mixture of ethyl acetate and methanol (90/10 by volume). Afterconcentration of the fractions under reduced pressure, 2.81 g of a brownoil are obtained, which oil is dissolved in 200 cm³ of ethanol and 6.25cm³ of an approximately 6M aqueous hydrochloric acid solution are added.The solution is concentrated to dryness under reduced pressure (3 kPa).The residue is taken up with 200 cm³ of ethanol and redried, twice. 3.01g of3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanedihydrochloride are thus obtained in the form of a beige foam.

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 1.90 (mt:4H); 2.06 (mt: 1H); from 2.50 to 2.65 (mt: 1H); 2.94 (dd, J=10 and 5 Hz:1H); from 3.10 to 3.40 (mt: 5H); 4.11 (dd, J=10.5 and 6 Hz: 1H); 4.16(dd J=10.5 and 6 Hz: 1H); 5.33 (s: 2H); 7.07 (broad t, J=7.5 Hz: 1H);7.36 (broad t, J=7.5 Hz: 3H); 7.43 (broad t, J=7.5 Hz: 2H); 7.50 (broadd, J=7.5. Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.14 (s: 1H); 10.51(unresolved peak: 1H).

IR spectrum (KBr): 3031; 2936; 2803; 2564; 1606; 1578; 1569; 1510; 1454;1435; 1360; 1046; 1024; 764; 697; 615 and 511 cm⁻¹.

The 3-benzyloxy-4-phenylpyrazole can be prepared in the following way:

A suspension of 5.7 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, 3.9g of potassium carbonate and 3.7 cm³ (5.3 g) of benzyl bromide in 250cm³ of 2-butanone is stirred at the boiling temperature of the reactionmedium for two and a quarter hours. The insoluble inorganic material isremoved by filtration and the filtrate is concentrated to dryness underreduced pressure (3 kPa). The residue is dissolved in 50 cm³ oftetrahydrofuran, 50 cm³ of methanol and 1 cm³ of a 10N sodium hydroxidesolution are added and the mixture is stirred for a quarter of an hourat ambient temperature and then concentrated to dryness under reducedpressure (3 kPa). The residue is taken up with 5 cm³ of water andextracted with 250 cm³ of ethyl acetate. The organic phase is dried overanhydrous magnesium sulfate, filtered and concentrated to dryness underreduced pressure (3 kPa), so as to give a white solid residue, which istriturated in a mixture of isopropyl ether and petroleum ether. Afterfiltration and air-drying, 4.43 g of 3-benzyloxy-4-phenylpyrazole areobtained in the form of a white solid which melts at 163° C.

EXAMPLE 43-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanehydrochloride monohydrate

0.99 g of sodium hydride (75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.9 g of 3-methoxy-4-phenylpyrazole in 15 cm³ ofanhydrous dimethylformamide. After stirring for three quarters of anhour at a temperature in the region of 50° C., 3.04 g of3-chloromethyl-1-azabicyclo[2.2.2]-octane hydrochloride are added insmall portions, and the mixture is then heated for 16 hours at atemperature in the region of 50° C. The mixture is cooled to ambienttemperature, 10 cm³ of water are then added slowly, and the mixture isconcentrated under reduced pressure (3 kPa). The residue is taken upwith 25 cm³ of water and extracted with 3 times 100 cm³ of ethylacetate. The pooled organic phases are washed with 3 times 25 cm³ ofwater, and then dried, filtered and concentrated to dryness underreduced pressure (3 kPa). The oily residue obtained is purified bychromatography on alumina, eluting with a mixture of ethyl acetate andmethanol (90/10 by volume). After concentration of the fractions underreduced pressure, 0.3 g of a brown oil is obtained, which is dissolvedin 40 cm³ of acetone, and 35 cm³ of approximately 3M hydrochloric etherare added. The solution is concentrated to dryness under reducedpressure (3 kPa) and the pasty residue is washed with two times 50 cm³of ethyl ether and then triturated in 50 cm³ of ethyl ether overnight.After filtration of the solid obtained and drying under vacuum (70 Pa)at a temperature of 60° C., 0.25 g of3-(3-methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanehydrochloride monohydrate is obtained in the form of a white powderwhich melts at around 125° C. (with decomposition). ¹H NMR spectrum (300MHz, (CD₃)₂SO d6, δ in ppm): from 1.60 to 1.90 (mt: 4H); 2.05(unresolved peak: 1H); from 2.45 to 2.60 (mt: 1H); 2.94 (broad dd, J=13and 7 Hz: 1H); from 3.05 to 3.40 (mt: 5H); 3.93 (s: 3H); 4.12 (mt: 2H);7.17 (broad t, J=7.5 Hz: 1H); 7.35 (broad t, J=7.5 Hz: 2H); 7.62 (broadd, J=7.5 Hz: 2H); 8.10 (s: 1H); from 9.40 to 9.90 (very broad unresolvedpeak: 1H).

IR spectrum (KBr): 2942; 2562; 1609; 1579; 1517; 1458; 1406; 1048; 1030;759; 698; 601 and 508 cm⁻¹.

EXAMPLE 5 1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 0.163 g of3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane, 0.38 cm³of 6M hydrochloric acid and 0.024 g of palladium-on-charcoal (at 10%) in20 cm³ of ethanol is stirred in an autoclave under a hydrogen pressureof 1 000 kPa, at a temperature of 20° C. for 8 hours. The reactionmedium is then filtered over Celite® and concentrated to dryness underreduced pressure (3 kPa), so as to give a hygroscopic oily residue,which is dissolved in 10 cm³ of water and lyophilized. 0.083 g of1-(1-azabicyclo-[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-1-oldihydrochloride is thus obtained in the form of an amorphous brownsolid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 2.05 (mt:4H); 2.41 (mt: 1H); 3.26 (mt: 3H); 3.40 (mt: 1H); 3.77 (mt: 2H); 4.68(mt: 1H); 7.15 (broad t, J=7.5 Hz: 1H); 7.34 (broad t, J=7.5 Hz: 2H);7.69 (broad d, J=7.5 Hz: 2H); 8.22 (s: 1H); from 10.15 to 10.75 (broadunresolved peak: 1H); 11.07 (unresolved peak: 1H).

IR spectrum (KBr): 3417; 2956; 2806; 2666; 1607; 1580; 1522; 1450; 1168;995; 762; 697; 671 and 513 cm¹.

The 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo-[2.2.2]octane canbe prepared in the following way:

0.96 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.5 g of 3-benzyloxy-4-phenylpyrazole in 30 cm³ ofanhydrous dimethylformamide. After stirring for three quarters of anhour at a temperature in the region of 50° C., a solution of 0.725 g of3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]octane in 5 cm³ of anhydrousdimethylformamide is added dropwise, and the mixture is then heated for20 hours at a temperature in the region of 110° C. The mixture is cooledto ambient temperature, 5 cm³ of water are then added slowly, and themixture is concentrated under reduced pressure (3 kPa). The residue istaken up with 10 cm³ of water and extracted with 50 cm³ of ethylacetate. The organic phase is washed with 3 times 10 cm³ of water, andis then dried, filtered and concentrated to dryness under reducedpressure (3 kPa). The oily residue obtained is purified by preparativeHPLC on 10μ C8 Kromasil, eluting with a mixture of acetonitrile andwater (50/50 by volume) and then of acetonitrile and ammoniacal methanol(7M) (98/2 by volume). After concentration of the fractions underreduced pressure, 0.163 g of3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane isobtained in the form of a yellow oil, which is used as it is in thefollowing step.

The 3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]octane can be obtainedaccording to the method described by S. M. Jenkins et al., J. Med. Chem.1992, 35, 2392-2406.

EXAMPLE 6 1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 0.65 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]perhydroazepine, 1.44 cm³of 6M hydrochloric acid and 0.092 g of palladium-on-charcoal (at 10%) in20 cm³ of ethanol is stirred in an autoclave under a hydrogen pressureof 1 000 kPa, at a temperature of 20° C. for 8 hours. The reactionmedium is then filtered over Celite® and concentrated to dryness underreduced pressure (3 kPa). The residue is triturated in 40 cm³ of acetoneand isolated by filtration. 0.541 g of1-(2-perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol dihydrochlorideis thus obtained in the form of a beige powder which melts at 228° C.(with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.64 (mt: 4H); 1.84(mt: 4H); 3.17 (mt: 2H); from 3.25 to 3.55 (mt: 4H); 4.41 (t, J=6.5 Hz:2H); 7.15 (broad t, J=7.5 Hz: 1H); 7.34 (broad t, J=7.5 Hz: 2H); 7.65(broad d, J=7.5 Hz: 2H); 8.05 (s: 1H); 10.35 (unresolved peak: 1H);10.49 (unresolved peak: 1H).

IR spectrum (KBr): 3431; 2934; 2638; 2422; 1608; 1582; 1572; 1528; 1452;1210; 1179; 1013; 760; 692; 673 and 511 cm⁻¹.

The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]perhydroazepine can beprepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.29 cm³ of perhydroazepine and 0.88 g of potassium carbonate in 25 cm³of acetonitrile is stirred for 3 hours at a temperature in the region of80° C., and then 0.15 cm³ of perhydroazepine is added and the heating iscontinued for 2 hours. The mixture is concentrated to dryness underreduced pressure (3 kPa). The residue is taken up with 50 cm³ of waterand extracted with 200 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, and is then dried, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel (particle size15-35 μm), eluting with a mixture of dichloromethane and methanol (96/4by volume). After concentration of the fractions under reduced pressure,0.72 g of 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]perhydroazepineis obtained in the form of a colorless viscous oil, which is used as itis in the following step. Mass spectrum (EI): m/z 375 (M^(+.)), m/z 112(base peak).

The1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethylcan be prepared in the following way:

59 cm³ of triethylamine are added dropwise, at ambient temperature, to asuspension of 13.7 g of 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanolhydrochloride in 400 cm³ of dichloromethane. The reaction mixture iscooled to around 5° C. and a solution of 22.5 g of toluene-4-sulfonylchloride in 200 cm³ of dichloromethane is added, over 0.5 hours. Afterstirring for 16 hours at ambient temperature, the mixture isconcentrated to dryness under reduced pressure (3 kPa). The residue istaken up with 100 cm³ of water and extracted with (500+250) cm³ of ethylacetate. The pooled organic phases are washed with 3 times 100 cm³ ofwater, and then dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel (particle size15-35 μm), eluting with dichloromethane and then a mixture ofdichloromethane and methanol (95/5 by volume). After concentration ofthe fractions under reduced pressure, 19 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethylare obtained in the form of a colorless viscous oil, which is used as itis in the following step. Mass spectrum (EI): m/z 448 (M^(+.)), m/z 91(base peak).

The 2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol can be prepared in thefollowing way:

750 cm³ of 37% hydrochloric acid are added, at ambient temperature, to asolution of 17 g of3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazole in750 cm³ of ethanol. After stirring for 2 hours at ambient temperature,the mixture is concentrated to dryness under reduced pressure (3 kPa).The residue is taken up with 1 dm³ of ethanol and concentrated todryness, 3 times, so as to give 13.8 g of2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethanol in the form of a solid whichmelts at 115° C., which is used as it is in the following step.

The3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazolecan be prepared in the following way: 3.07 g of sodium hydride (at 75%by mass in liquid petroleum jelly) are added gradually, under an argonatmosphere and at ambient temperature, to a solution of 16 g of3-benzyloxy-4-phenylpyrazole in 110 cm³ of anhydrous dimethylformamide.After stirring for three quarters of an hour at a temperature in theregion of 50° C., a solution of 11.06 cm³ (15.31 g) of2-(2-bromoethoxy)tetrahydropyran in 40 cm³ of anhydrousdimethylformamide is added dropwise, and the mixture is then heated forthree quarters of an hour at a temperature in the region of 50° C. 25cm³ of water are then added slowly to the mixture, which is then runinto 90 cm³ of water and extracted with 3 times 300 cm³ of ethylacetate. The pooled organic phases are washed with 3 times 100 cm³ ofwater, and then dried, filtered and concentrated to dryness underreduced pressure (3 kPa). The oily residue obtained is purified bychromatography on silica gel (particle size 20-45 μm), eluting with amixture of dichloromethane and ethyl acetate (90/10 by volume). Afterconcentration of the fractions under reduced pressure, 17.35 g of3-benzyloxy-4-phenyl-1-[2-(tetrahydropyran-2-yloxy)ethyl]-1H-pyrazoleare obtained in the form of a colorless pasty solid, which is used as itis in the following step.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.75 (mt:6H); from 3.25 to 3.45 (mt: 1H); 3.60 (ddd, J=11.5-8.5 and 3 Hz: 1H);3.72 (mt: 1H); 3.94 (ddd, J=10.5-6 and 4.5 Hz: 1H); 4.16 (mt: 2H); 4.55(mt: 1H); 5.32 (s: 2H); 7.14 (tt, J=7.5 and 1.5 Hz: 1H); from 7.25 to7.45 (mt: 3H); 7.33 (broad t, J=7.5 Hz: 2H); 7.50 (broad d, J=7.5 Hz:2H); 7.63 (broad d, J=7.5 Hz: 2H); 8.05 (s: 1H).

EXAMPLE 7 1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 0.58 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidine, 1.29cm³ of 6M hydrochloric acid and 0.082 g of palladium-on-charcoal (at10%) in 20 cm³ of ethanol is stirred in an autoclave under a hydrogenpressure of 1 000 kPa, at a temperature of 20° C. for 8 hours. Thereaction medium is then filtered over Celite® and concentrated todryness under reduced pressure (3 kPa). The residue is triturated in 40cm³ of acetone and isolated by filtration. 0.54 g of1-[2-(2-methylpiperidin-1-yl)-ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a beige powder whichmelts at 118° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with addition of a few drops ofCD₃COOD d4, δ in ppm): 1.29 (d, J=6.5 Hz: 3H); from 1.35 to 1.95 (mt:6H); 3.04 (ddd, J=12-9 and 3.5 Hz: 1H); from 3.30 to 3.50 (mt: 3H); from3.50 to 3.65 (mt: 1H); 4.37 (t, J=6.5 Hz: 2H); 7.14 (broad t, J=7.5 Hz:1H); 7.33 (broad t, J=7.5 Hz: 2H); 7.64 (broad d, J=7.5 Hz: 2H); 8.02(s: 1H).

IR spectrum (KBr): 3051; 2949; 2653; 2565; 1606; 1581; 1522; 1441; 1228;1171; 995; 768; 700; 671 and 587 cm⁻¹.

The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidine canbe prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.46 cm³ of 2-methylpiperidine and 0.88 g of potassium carbonate in 25cm³ of acetonitrile is stirred for 6 hours at a temperature in theregion of 80° C. The mixture is concentrated to dryness under reducedpressure (3 kPa). The residue is taken up with 50 cm³ of water andextracted with 200 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, and is then dried, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel (particle size15-35 μm), eluting with a mixture of dichloromethane and methanol (97/3by volume). After concentration of the fractions under reduced pressure,0.65 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-methylpiperidine isobtained in the form of a colorless viscous oil, which is used as it isin the following step.

Mass spectrum (EI): m/z 375 (M+), m/z 112 (base peak).

EXAMPLE 8 1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 0.5 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-fluoropiperidine, 1.1cm³ of 6M hydrochloric acid and 0.071 g of palladium-on-charcoal (at10%) in 20 cm³ of ethanol is stirred in an autoclave under a hydrogenpressure of 1 000 kPa, at a temperature of 20° C. for 8 hours. Thereaction medium is then filtered through Celite® and concentrated todryness under reduced pressure (3 kPa). The residue is triturated in 40cm³ of acetone and isolated by filtration. 0.54 g of1-[2-(4-fluoropiperidin-1-yl)-ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a beige powder whichmelts at 228° C. (with decomposition).

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few drops ofCD₃COOD d4, δ in ppm): from 2.00 to 2.25 (mt: 4H); 3.29 (unresolvedpeak: 4H); 3.52 (t, J=6 Hz: 2H); 4.40 (t, J=6 Hz: 2H); 4.94 (broad d,J=48 Hz: 1H); 7.14 (broad t, J=7.5 Hz: 1H); 7.33 (broad t, J=7.5 Hz:2H); 7.65 (broad d, J=7.5 Hz: 2H); 7.99 (s: 1H).

IR spectrum (KBr): 3054; 2963; 2633; 2531; 1608; 1582; 1528; 1452; 1177;1031; 1015; 764; 698 and 509 cm⁻¹.

The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-fluoropiperidine canbe prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.702 g of 4-fluoropiperidine hydrobromide and 1.18 g of potassiumcarbonate in 25 cm³ of acetonitrile is stirred for 6 hours at atemperature in the region of 80° C. The mixture is concentrated todryness under reduced pressure (3 kPa). The residue is taken up with 50cm³ of water and extracted with 200 cm³ of ethyl acetate. The organicphase is washed with 3 times 25 cm³ of water, and is then dried,filtered and concentrated to dryness under reduced pressure (3 kPa). Theoily residue obtained is purified by chromatography on silica gel(particle size 15-35 μm), eluting with a mixture of dichloromethane andmethanol (98.5/1.5 by volume). After concentration of the fractionsunder reduced pressure, 0.61 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-4-fluoropiperidine isobtained in the form of a colorless viscous oil, which is used as it isin the following step.

Mass spectrum (EI): m/z 379 (M^(+.)), m/z 250 and m/z 116 (base peak).

EXAMPLE 9 1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 0.57 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidine, 1.27cm³ of 6M hydrochloric acid and 0.081 g of palladium-on-charcoal (at10%) in 20 cm³ of ethanol is stirred in an autoclave under a hydrogenpressure of 1 000 kPa, at a temperature of 20° C. for 8 hours. Thereaction medium is then filtered over Celite® and concentrated todryness under reduced pressure (3 kPa). The residue is triturated in 75cm³ of acetone and isolated by filtration. 0.198 g of1-[2-(3-methylpiperidin-1-yl)-ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a pale yellow powderwhich melts at 220° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with addition of a few drops ofCD₃COOD, δ in ppm): 0.89 (d, J=7 Hz: 3H); 1.05 (mt: 1H); from 1.60 to2.00 (mt: 4H); 2.58 (mt: 1H); 2.83 (very broad t, J=12 Hz: 1H); from3.30 to 3.55 (mt: 4H); 4.39 (t, J=6.5 Hz: 2H); 7.13 (broad t, J=7.5 Hz:1H); 7.32 (broad t, J=7.5 Hz: 2H); 7.63 (broad d, J=7.5 Hz: 2H); 7.99(s: 1H).

IR spectrum (KBr): 3057; 2960; 2651; 2550; 1607; 1581; 1523; 454; 1179;761; 697; 614 and 513 cm⁻¹.

The 1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidine canbe prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.46 cm³ of 3-methylpiperidine and 0.88 g of potassium carbonate in 25cm³ of acetonitrile is stirred for 6 hours at a temperature in theregion of 80° C. The mixture is concentrated to dryness under reducedpressure (3 kPa). The residue is taken up with 50 cm³ of water andextracted with 200 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, and is then dried, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel (particle size15-35 μm), eluting with a mixture of dichloromethane and methanol (97/3by volume). After concentration of the fractions under reduced pressure,0.58 g of1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-3-methylpiperidine isobtained in the form of a colorless viscous oil, which is used as it isin the following step.

Mass spectrum (EI): m/z 375 (M^(+.)), m/z 112 (base peak)

EXAMPLE 101-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

A solution of 0.6 g of1-[2-(3-benzyloxy-4-phenylpyrrol-1-yl)ethyl]-1,2,3,6-tetrahydropyridinein a mixture of 5 cm³ of 37% hydrochloric acid and of 5 cm³ of ethanolis heated at 80° C. for 6 hours and then concentrated to dryness underreduced pressure (3 kPa). The residue is taken up with 100 cm³ ofethanol and concentrated to dryness, 4 times. The residue is trituratedin 40 cm³ of acetone and isolated by filtration. 0.403 g of1-[2-(3,6-dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a brown powder whichmelts at 192° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.29 (very broad d,J=18 Hz: 1H); from 2.40 to 2.60 (mt: 1H); 3.07 (mt: 1H); 3.47 (mt: 1H);3.55 (mt: 2H); 3.62 (very broad d, J=16.5 Hz: 1H); 3.84 (broad d, J=16.5Hz: 1H); 4.47 (t, J=6.5 Hz: 2H); 5.72 (broad d, J=10.5 Hz: 1H); 5.93(very broad d, J=10.5 Hz: 1H); 7.15 (broad t, J=7.5 Hz: 1H); 7.34 (broadt, J=7.5 Hz: 2H); 7.66 (broad d, J=7.5 Hz: 2H); 8.06 (s: 1H); from 10.20to 10.80 (broad unresolved peak: 1H); 10.88 (unresolved peak: 1H).

IR spectrum (KBr): 3422; 2948; 2688; 2579; 1607; 1526; 1452; 1184; 1023;768; 699; 667; 670 and 511 cm⁻¹.

The1-[2-(3-benzyloxy-4-phenylpyrrol-1-yl)ethyl]-1,2,3,6-tetrahydropyridinecan be prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.36 cm³ of 1,2,3,6-tetrahydropyridine and 0.88 g of potassium carbonatein 25 cm³ of acetonitrile is stirred for 6 hours at a temperature in theregion of 80° C. The mixture is concentrated to dryness under reducedpressure (3 kPa). The residue is taken up with 50 cm³ of water andextracted with 200 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, and is then dried, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel (particle size15-35 μm), eluting with a mixture of dichloromethane and methanol (97/3by volume). After concentration of the fractions under reduced pressure,0.6 g of1-[2-(3-benzyloxy-4-phenylpyrrol-1-yl)ethyl]-1,2,3,6-tetrahydropyridineis obtained in the form of a colorless viscous oil, which is used as itis in the following step.

Mass spectrometry (CI): m/z 360 ([M+H]⁺) (base peak).

EXAMPLE 111-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

3 cm³ of 1M hydrochloric acid are added to a solution of 0.6 g of7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2.2.1]heptanein 40 cm³ of ethanol and the mixture is stirred for a quarter of an hourat ambient temperature and then concentrated to dryness under reducedpressure (3 kPa). The residue obtained and 0.078 g ofpalladium-on-charcoal (at 10%) are suspended in 20 cm³ of ethanol andstirred in an autoclave under a hydrogen pressure of 1 000 kPa, at atemperature of 20° C. for 8 hours. The reaction medium is then filteredover Celite® and concentrated to dryness under reduced pressure (3 kPa).The residue is triturated in 25 cm³ of acetone and isolated byfiltration. 0.466 g of1-[2-(7-azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a white powder whichmelts at 228° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.66 (unresolved peak:4H); 2.00 (unresolved peak: 4H); 3.43 (mt: 2H); 3.93 (broad s: 2H); 4.43(broad t, J=6.5 Hz: 2H); 7.15 (broad t, J=7.5 Hz: 1H); 7.35 (broad t,J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.08 (s: 1H); from 10.35 to10.55 (broad unresolved peak: 1H); 10.47 (unresolved peak: 1H).

IR spectrum (KBr): 2988; 2789; 2661; 2537; 1608; 1533; 1449; 1279; 1179;875; 761; 698; 674 and 510 cm⁻¹.

The7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2.2.1]heptanecan be prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.616 g of 7-azabicyclo[2.2.1]heptane hydrochloride and 0.88 g ofpotassium carbonate in 25 cm³ of acetonitrile is stirred for 5 hours ata temperature in the region of 80° C. The mixture is concentrated todryness under reduced pressure (3 kPa). The residue is taken up with 30cm³ of water and extracted with 250 cm³ of ethyl acetate. The organicphase is washed with 3 times 30 cm³ of water, and is then dried,filtered and concentrated to dryness under reduced pressure (3 kPa). Theoily residue obtained is purified by chromatography on silica gel(particle size 15-35 μm), eluting with a mixture of dichloromethane andmethanol (98/2 by volume). After concentration of the fractions underreduced pressure, 0.6 g of7-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-7-azabicyclo[2.2.1]heptaneis obtained in the form of a colorless viscous oil, which is used as itis in the following step.

Mass spectrum (CI): m/z 374 ([M+H]⁺) (base peak).

EXAMPLE 121-[2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

2 cm³ of 6M hydrochloric acid is added to a solution of 0.9 g of2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2.2.2]octanein 50 cm³ of ethanol, and the mixture is stirred for a quarter of anhour at ambient temperature and then concentrated to dryness underreduced pressure (3 kPa). The residue obtained and 0.124 g ofpalladium-on-charcoal (at 10%) are suspended in 20 cm³ of ethanol andstirred in an autoclave under a hydrogen pressure of 1 000 kPa, at atemperature of 20° C. for 8 hours. The reaction medium is then filteredover Celite® and concentrated to dryness under reduced pressure (3 kPa).The residue is triturated in 25 cm³ of acetone and isolated byfiltration. 0.56 g of1-[2-(2-azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a beige powder whichmelts at 171° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.50 to 1.75 (mt:6H); 1.90 (very broad s: 1H); from 2.00 to 2.15 (mt: 1H); 2.28 (mt: 1H);2.86 (very broad dd, J=12 and 4.5 Hz: 1H); from 3.35 to 3.55 (mt: 1H);3.38 (very broad s: 1H); 3.55 (broad t, J=6.5 Hz: 2H); 4.46 (broad t,J=6.5 Hz: 2H); 7.14 (broad t, J=7.5 Hz: 1H); 7.34 (broad t, J=7.5 Hz:2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.04 (s: 1H); 10.84 (unresolved peak:1H).

IR spectrum (KBr): 2949; 2870; 2629; 2184; 1608; 1579; 1510; 1455; 1198;870; 761; 692; 670 and 510 cm⁻¹.

The2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2.2.2]octanecan be prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.563 g of 2-azabicyclo[2.2.2]octane hydrochloride and 0.88 g ofpotassium carbonate in 25 cm³ of acetonitrile is stirred for 8 hours ata temperature in the region of 80° C. The mixture is concentrated todryness under reduced pressure (3 kPa). The residue is taken up with 30cm³ of water and extracted with 200 cm³ of ethyl acetate. The organicphase is washed with twice 30 cm³ of water, and is then dried, filteredand concentrated to dryness under reduced pressure (3 kPa). The oilyresidue obtained is purified by chromatography on silica gel (particlesize 15-35 am), eluting with a mixture of dichloromethane and methanol(95/5 by volume). After concentration of the fractions under reducedpressure, 0.92 g of2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2.2.2]octaneis obtained in the form of a colorless viscous oil, which is used as itis in the following step.

Mass spectrum (CI): m/z 388 ([M+H]⁺) (base peak).

The 2-azabicyclo[2.2.2]octane hydrochloride can be obtained according tothe method described by M. Yokota et al., Eur. J. Med. Chem. Chim.Ther., 1997, 32 (5), 377-384.

EXAMPLE 131-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

1.6 cm³ of 6M hydrochloric acid are added to a solution of 0.7 g of2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2.2.1]heptanein 50 cm³ of ethanol, and the mixture is stirred for a quarter of anhour at ambient temperature and then concentrated to dryness underreduced pressure (3 kPa). The residue obtained and 0.10 g ofpalladium-on-charcoal (at 10%) are suspended in 20 cm³ of ethanol andstirred in an autoclave under a hydrogen pressure of 1 000 kPa, at atemperature of 20° C. for 8 hours. The reaction medium is then filteredover Celite® and concentrated to dryness under reduced pressure (3 kPa).The residue is triturated in 40 cm³ of acetone and isolated byfiltration. 0.565 g of1-[2-(2-azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a beige powder whichmelts at 173° C. (with decomposition).

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 with addition of a few drops ofCD₃COOD d4, at a temperature of 363 K, δ in ppm): from 1.45 to 1.55 (mt:1H); from 1.65 to 1.80 (mt: 3H); from 1.95 to 2.05 (mt: 2H); 2.65 (mt:1H); from 3.10 to 3.25 (broad unresolved peak: 2H); 3.48 (mt: 1H); 3.59(mt: 1H); 4.04 (mt: 1H); 4.34 (broad t, J=6.5 Hz: 2H); 7.15 (broad t,J=7.5 Hz: 1H); 7.32 (broad t, J=7.5 Hz: 2H); 7.62 (broad d, J=7.5 Hz:2H); 7.90 (s: 1H).

IR spectrum (KBr): 2955; 2827; 2601; 2554; 1607; 1528; 1454; 1177; 1010;767; 699; 672 and 515 cm⁻¹.

The2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2-azabicyclo[2.2.1]heptanecan be prepared in the following way:

A suspension of 1 g of1-[(toluene-4-sulfonyl)oxy]-2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl,0.51 g of 2-azabicyclo[2.2.1]heptane hydrochloride and 0.88 g ofpotassium carbonate in 25 cm³ of acetonitrile is stirred for 8 hours ata temperature in the region of 80° C. The mixture is concentrated todryness under reduced pressure (3 kPa). The residue is taken up with 30cm³ of water and extracted with 200 cm³ of ethyl acetate. The organicphase is washed with two times 30 cm³ of water, and is then dried,filtered and concentrated to dryness under reduced pressure (3 kPa). Theoily residue obtained is purified by chromatography on silica gel(particle size 15-35 μm), eluting with a mixture of dichloromethane andmethanol (95/5 by volume). After concentration of the fractions underreduced pressure, 0.75 g of2-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-ethyl]-2-azabicyclo[2.2.1]heptaneis obtained in the form of a colorless viscous oil, which is used as itis in the following step.

Mass spectrum (EI): m/z 373 (M^(+.)), m/z 110 (base peak).

The 2-azabicyclo[2.2.1]heptane hydrochloride can be obtained accordingto the method described by J. R. Malpass et al., J.C.S., Perkin Trans. 11977, 8, 874-884.

EXAMPLE 14 1-[2-Dimethylaminoethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.10 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-dimethylaminedihydrochloride and 0.012 g of palladium-on-charcoal (at 10%). 0.049 gof 1-[2-dimethylamino-ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride isthus obtained in the form of a beige powder which melts at around 135°C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.81 (d, J=5 Hz: 6H);3.51 (mt: 2H); 4.38 (t, J=6.5 Hz: 2H); 7.16 (broad t, J=7.5 Hz: 1H);7.35 (broad t, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.05 (s:1H); 10.27 (unresolved peak: 1H); from 10.30 to 10.70 (very broadunresolved peak: 1H).

IR spectrum (KBr): 3311; 2985; 2558; 2463; 1629; 1582; 1508; 1467; 1409;1190; 985; 760; 687 and 673 cm⁻¹.

The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]dimethylaminedihydrochloride can be prepared in the following way:

0.154 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazole in 3 cm³ ofanhydrous dimethylformamide, followed, after disappearance of the foams,by 0.5 g of (2-bromoethyl)-dimethylamine hydrobromide. After stirringfor 2 hours at ambient temperature, water is slowly added and themixture is extracted with ethyl acetate. The organic phase is dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (3 kPa). The oily residue obtained is purified bychromatography on silica gel, eluting with a mixture of dichloromethane,methanol and aqueous ammonia at 28% (90/8/2 by volume). Afterconcentration of the fractions under reduced pressure, 0.21 g of an oilis obtained, which is dissolved in ethyl ether, has 1 cm³ of anapproximately 3M hydrochloric ether solution added to it, and isreturned to dryness. The residue is triturated in acetone and thenisolated by filtration. 0.1 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-dimethylaminedihydrochloride is thus obtained in the form of white crystals whichmelt at 105° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.82 (d, J=5 Hz: 6H);3.57 (mt: 2H); 4.34 (t, J=6.5 Hz: 2H); 5.36 (s: 2H); 7.18 (broad t,J=7.5 Hz: 1H); from 7.30 to 7.50 (mt: 5H); 7.52 (broad d, J=7.5 Hz: 2H);7.65 (broad d, J=7.5 Hz: 2H); 8.17 (s: 1H); 9.68 (unresolved peak: 1H).

The (2-bromoethyl)dimethylamine hydrobromide can be obtained accordingto the method described by L. H. Amundsen et al., J. Am. Chem. Soc.1941, 63, 305-307.

EXAMPLE 15 1-[3-Dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.274 g of[3-(3-benzyloxy-4-phenylpyrazol-1-yl)-propyl]dimethylaminedihydrochloride and 0.04 g of palladium-on-charcoal (at 10%). 0.209 g of1-[3-dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride isthus obtained in the form of a beige powder which melts at around 208°C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.20 (mt: 2H); 3.5 (d,J=5 Hz: 6H); 3.07 (mt: 2H); 4.04 (t, J=6.5 Hz: 2H); 7.13 (broad t, J=7.5Hz: 1H); 7.33 (broad t, J=7.5 Hz: 2H); 7.66 (broad d, J=7.5 Hz: 2H);7.99 (s: 1H); 10.82 (unresolved peak: 1H).

IR spectrum (KBr): 3078; 2954; 2591; 2470; 1603; 1476; 1369; 1268; 1188;881; 763; 700; 570 and 494 cm⁻¹.

The [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminedihydrochloride can be prepared in the following way:

3.6 cm³ of 1N sodium hydroxide solution are added to a suspension of0.38 g of [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylamineoxalate in 10 cm³ of water and the mixture is stirred for a quarter ofan hour and then extracted with 3 times 25 cm³ of ethyl acetate. Thepooled organic phases are dried over magnesium sulfate, and thenconcentrated to dryness under reduced pressure (3 kPa). The residueobtained is dissolved in 25 cm³ of ethanol, an excess of anapproximately 3M hydrochloric ether solution is added, and the mixtureis returned to dryness. 0.274 g of[3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylaminedihydrochloride is thus obtained in the form of a pasty white solid usedas it is in the following step.

The [3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylamine oxalatecan be prepared in the following way:

0.106 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazole in 15 cm³ ofanhydrous dimethylformamide. After stirring for three quarters of anhour at a temperature in the region of 50° C., 0.316 g of(3-chloropropyl)dimethylamine hydrochloride is added in small portionsand the mixture is then stirred for 16 hours at ambient temperature. Themixture is run into 150 cm³ of water and extracted with 3 times 150 cm³of ethyl acetate. The pooled organic phases are washed with 50 cm³ ofwater, and are then dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained (0.8 g) is dissolved in 10 cm³ of ethyl ether and a solution of0.09 g of oxalic acid in 5 cm³ of ethyl ether is added. The whiteprecipitate formed is filtered and then dried under vacuum (70 Pa) atambient temperature. 0.395 g of[3-(3-benzyloxy-4-phenylpyrazol-1-yl)propyl]dimethylamine oxalate isthus obtained in the form of a white solid used as it is in thefollowing step.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.15 (mt: 2H); 30 (s:6H); 2.98 (mt: 2H); 4.08 (t, J=6.5 Hz: 2H); 5.33 (s: 2H); 7.16 (broad t,J=7.5 Hz: 1H); from 7.30 to 7.45 (mt: 3H); 7.43 (broad t, J=7.5 Hz: 2H);7.51 (broad d, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.09 (s:1H).

EXAMPLE 161-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)-ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.123 g of(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidinedihydrochloride and 0.014 g of palladium-on-charcoal (at 10%). 0.075 gof1-[2-((2S,6R)-2,6-dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride is thus obtained in the form of a beige powder whichmelts at around 206° C. (with decomposition).

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, at a temperature of 403K, δ inppm): 1.36 (d, J=6.5 Hz: 6H); 1.57 (mt: 1H); from 1.65 to 1.90 (mt: 5H);3.28 (unresolved peak: 2H); 3.49 (unresolved peak: 2H); 4.36 (broad t,J=6.5 Hz: 2H); 7.15 (tt, J=7.5 and 1.5 Hz: 1H); 7.33 (broad t, J=7.5 Hz:2H); 7.66 (broad d, J=7.5 Hz: 2H); 8.00 (S: 1H).

IR spectrum (KBr): 3428; 3058; 2978; 2942; 2657; 2571; 1606; 1580; 1521;1452; 1388; 1173; 997; 914; 766; 699; 671 and 511 cm⁻¹.

The(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-ethyl]-2,6-dimethylpiperidinedihydrochloride can be prepared in the following way:

0.5 cm³ of an approximately 3M hydrochloric ether solution is added to asolution of 0.117 g of(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidinein 25 cm³ of ethanol, which is then brought back to dryness. 0.123 g of(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidinedihydrochloride is thus obtained in the form of a colorless paste usedas it is in the following step.

The(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-ethyl]-2,6-dimethylpiperidinecan be prepared in the following way:

0.211 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.25 g of 3-benzyloxy-4-phenylpyrazole in 20 cm³ ofanhydrous dimethylformamide. After stirring for three quarters of anhour at a temperature in the region of 50° C., 0.636 g of(2S,6R)-1-(2-chloroethyl)-2,6-dimethylpiperidine hydrochloride is addedin small portions, and the mixture is then stirred for 16 hours atambient temperature. The mixture is run into 150 cm³ of water andextracted with twice 150 cm³ of ethyl acetate. The pooled organic phasesare washed with 50 cm³ of water, and are then dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (3 kPa). The oily residue obtained is dissolved in 25 cm³ ofethyl ether and a solution of 0.09 g of oxalic acid in 25 cm³ of ethylether is added. The pasty product formed is washed with 3 times 25 cm³of ethyl ether, and is then taken up with 25 cm³ of water, 4 cm³ of 1Nsodium hydroxide solution are added, and the mixture is stirred for aquarter of an hour and then extracted with two times 25 cm³ of ethylacetate. The pooled organic phases are dried over magnesium sulfate, andthen concentrated to dryness under reduced pressure (3 kPa). The oilyresidue obtained is purified by chromatography on silica gel, elutingwith a mixture of ethyl acetate and methanol (80/20 by volume). Afterconcentration of the fractions under reduced pressure, 0.117 g of(2S,6R)-1-[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-2,6-dimethylpiperidineis obtained in the form of a colorless oil used as it is in thefollowing step. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.08(d, J=6.5 Hz: 6H); 1.17 (broad double t, J=12 and 3 Hz: 2H); 1.28 (mt:1H); 1.53 (broad d, J=12 Hz: 2H); 1.62 (mt: 1H); 2.48 (mt: 2H); 2.95 (t,J=6.5 Hz: 2H); 3.98 (t, J=6.5 Hz: 2H); 5.32 (s: 2H); 7.15 (tt, J=7.5 and1.5 Hz: 1H); from 7.30 to 7.45 (mt: 1H); 7.34 (broad t, J=7.5 Hz: 2H);7.42 (broad t, J=7.5 Hz: 2H); 7.52 (broad d, J=7.5 Hz: 2H); 7.66 (broadd, J=7.5 Hz: 2H); 8.10 (s: 1H).

The (2S,6R)-1-(2-chloroethyl)-2,6-dimethylpiperidine-amine hydrochloridecan be obtained according to the method described by R. Dahlbom et al.,Acta Pharmaceutica Suecica 1969, 6 (3), 413-418.

EXAMPLE 17 1-[2-Diethylaminoethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.31 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine dihydrochlorideand 0.04 g of palladium-on-charcoal (at 10%). 0.139 g of1-[2-diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochloride is thusobtained in the form of a white powder which melts at around 174° C.(with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.23 (t, J=7 Hz: 6H);3.12 (very broad q, J=7 Hz: 4H); 3.46 (very broad t, J=6.5 Hz: 2H); 4.40(broad t, J=6.5 Hz: 2H); 7.14 (broad t, J=7.5 Hz: 1H); 7.33 (broad t,J=7.5 Hz: 2H); 7.65 (broad d, J.=7.5 Hz: 2H); 8.07 (s: 1H); 10.46(unresolved peak: 1H); from 10.60 to 10.85 (broad unresolved peak: 1H).

IR spectrum (KBr): 3065; 2974; 2589; 2484; 1609; 1530; 1454; 1179; 1012;765; 693; 677 and 508 cm⁻¹.

The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminedihydrochloride can be obtained in the following way:

The process is carried out as in example 15, but with 0.31 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)-ethyl]diethylamine oxalate. 0.31 gof [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylaminedihydrochloride is thus obtained in the form of a colorless gum used asit is in the following step.

The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine oxalate canbe obtained in the following way:

The process is carried out as in example 15, but with 0.211 g of sodiumhydride (at 75% by mass in liquid petroleum jelly) and 0.516 g of(2-chloroethyl)diethylamine hydrochloride. 0.376 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine oxalate is thusobtained in the form of a white powder which melts at 133° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.12 (t, J=7 Hz: 6H);2.98 (broad q, J=7 Hz: 4H); 3.35 (very broad t, J=6.5 Hz: 2H); 4.31(broad t, J=6.5 Hz: 2H); 5.35 (s: 2H); 7.17 (broad t, J=7.5 Hz: 1H);7.36 (mt: 3H); 7.43 (broad t, J=7.5 Hz: 2H); 7.51 (broad d, J=7.5 Hz:2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.14 (s: 1H).

EXAMPLE 18 1-(2-Diisopropylaminoethyl)-4-phenyl-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.21 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-diisopropylaminedihydrochloride and 0.025 g of palladium-on-charcoal (at 10%). 0.122 gof 1-[2-diisopropylamino-ethyl]-4-phenyl-1H-pyrazol-3-ol dihydrochlorideis thus obtained in the form of a beige powder which melts at around220° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.32 (broad d, J=7 Hz:6H); 1.34 (broad d, J=7 Hz: 6H); 3.47 (unresolved peak: 2H); 3.71 (mt:2H); 4.40 (broad t, J=6.5 Hz: 2H); 7.14 (broad t, J=7.5 Hz: 1H); 7.33(broad t, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.12 (s: 1H);9.96 (unresolved peak: 1H); 10.49 (broad s: 1H).

IR spectrum (KBr): 2984; 2654; 2507; 2469; 1607; 1580; 1531; 1453; 1193;759; 693; 673 and 511 cm⁻¹.

The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminedihydrochloride can be obtained in the following way:

The process is carried out as in example 15, but with 0.31 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]-diisopropylamine oxalate.0.21 g of [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylaminedihydrochloride is thus obtained in the form of a beige semi-solid usedas it is in the following step.

The [2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diisopropylamine oxalatecan be obtained in the following way:

The process is carried out as in example 15, but with 0.211 g of sodiumhydride (at 75% by mass in liquid petroleum jelly) and 0.6 g of(2-chloroethyl)diisopropylamine hydrochloride. 0.312 g of[2-(3-benzyloxy-4-phenylpyrazol-1-yl)ethyl]diethylamine oxalate is thusobtained in the form of a white powder which melts at 134° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with addition of a few drops ofCD₃COOD d4, δ in ppm): 1.21 (d, J=6 Hz: 12H); 3.39 (broad t, J=6.5 Hz:2H); 3.57 (mt: 2H); 4.30 (t, J=6.5 Hz: 2H); 5.35 (s: 2H); 7.17 (broad t,J=7.5 Hz: 1H); 7.35 (mt: 3H); 7.41 (broad t, J=7.5 Hz: 2H); 7.49 (broadd, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.10 (s: 1H).

EXAMPLE 19 4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

The process is carried out as in example 2, but with 0.285 g of3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazoledihydrochloride and 0.037 g of palladium-on-charcoal (at 10%). 0.101 gof 4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol dihydrochlorideis thus obtained in the form of a beige powder which melts at around173° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.80 to 2.10 (mt:4H); from 2.90 to 3.10 (unresolved peak: 2H); from 3.45 to 3.65(unresolved peak: 4H); 4.34 (broad t, J=6.5 Hz: 2H); 7.14 (broad t,J=7.5 Hz: 1H); 7.33 (broad t, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz:2H); 8.02 (s: 1H); from 10.30 to 10.60 (broad unresolved peak: 1H);10.43 (unresolved peak: 1H).

IR spectrum (KBr): 3416; 3054; 2973; 2670; 2585; 2476; 2405; 1608; 1581;1527; 1453; 1247; 1175; 1011; 768; 702; 673 and 514 cm⁻¹.

The 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazoledihydrochloride can be obtained in the following way:

The process is carried out as in example 15, but with 0.34 g of3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazole oxalate.0.285 g of 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazoledihydrochloride is thus obtained in the form of a beige gum used as itis in the following step.

The 3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazole oxalatecan be obtained in the following way:

The process is carried out as in example 15, but with 0.211 g of sodiumhydride (at 75% by mass in liquid petroleum jelly) and 0.51 g of1-(2-chloroethyl)pyrrolidine hydrochloride. 0.354 g of3-benzyloxy-4-phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazole oxalate isthus obtained in the form of a white powder which melts at 144° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.87 (mt: 4H); 3.10(mt: 4H); 3.46 (mt: 2H); 4.33 (t, J=6.5 Hz: 2H); 5.35 (s: 2H); 7.18(broad t, J=7.5 Hz: 1H); 7.36 (mt: 3H); 7.43 (broad t, J=7.5 Hz: 2H);7.52 (broad d, J=7.5 Hz: 2H); 7.66 (broad d, J=7.5 Hz: 2H); 8.13 (s:1H).

EXAMPLE 20 3-(3-Methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]-octanehydrochloride

1.94 g of potassium tert-butoxide are added gradually, under an argonatmosphere and at ambient temperature, to a solution of 1.2 g of3-methoxy-4-phenylpyrazole in 20 cm³ of anhydrous dimethylformamide.After stirring for 1.5 hours at ambient temperature, a solution of 2.8 gof 3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]-octane in 20 cm³ ofanhydrous dimethylformamide is added dropwise, and the mixture is thenheated for 16 hours at a temperature in the region of 100° C. Themixture is cooled to ambient temperature and is then concentrated underreduced pressure (3 kPa). The residue is taken up with 30 cm³ of waterand extracted with 250 cm³ of ethyl acetate. The organic phase is washedwith 3 times 30 cm³ of water, and dried, filtered and concentrated todryness under reduced pressure (3 kPa). The oily residue obtained ispurified by chromatography on silica gel, eluting with a mixture ofethyl acetate and methanol (90/10, then 75/25 by volume). Afterconcentration of the fractions under reduced pressure, 0.36 g of an oilis obtained, which is dissolved in 15 cm³ of acetone, and 5 cm³ of anapproximately 1M hydrochloric ether solution are added. The precipitatewhich has appeared is triturated overnight and then isolated byfiltration. 0.308 g of3-(3-methoxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octanehydrochloride is thus obtained in the form of a hygroscopic beige powderwhich melts at around 207° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 2.05 (mt:4H); 2.42 (mt: 1H); 3.28 (mt: 3H); from 3.35 to 3.55 (mt: 1H); 3.80 (mt:2H); 3.97 (s: 3H); 4.75 (mt: 1H); 7.18 (broad t, J=7.5 Hz: 1H); 7.36(broad t, J=7.5 Hz: 2H); 7.65 (broad d, J=7.5 Hz: 2H); 8.30 (s: 1H);10.76 (unresolved peak: 1H).

IR spectrum (KBr): 3430; 2939; 2907; 2666; 2584; 1607; 1580; 1570; 1518;1454; 1409; 1049; 1028; 764; 698; 623 and 513 cm⁻¹.

EXAMPLE 211-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]-piperidinehydrochloride

The process is carried out as in example 1, but with 0.25 g of3-difluoromethoxy-4-phenyl-1H-pyrazole, 0.303 g of sodium hydride (at75% by mass in liquid petroleum jelly) and 0.6 g of1-(2-chloroethyl)piperidine hydrochloride, and then eluting with amixture of dichloromethane and methanol (95/5 by volume). 0.175 g of1-[2-(3-difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]piperidinehydrochloride is thus obtained in the form of a white solid which meltsat around 174° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (unresolved peak:1H); from 1.60 to 1.90 (mt: 5H); 2.94 (unresolved peak: 2H); 3.47 (verybroad d, J=12 Hz: 2H); 3.54 (unresolved peak: 2H); 4.55 (broad t, J=6.5Hz: 2H); 7.29 (tt, J=7.5 and 2.5 Hz: 1H); 7.41 (t, J=72 Hz: 1H); 7.44(broad t, J=7.5 Hz: 2H); 7.59 (broad d, J=7.5 Hz: 2H); 8.30 (s: 1H);from 10.00 to 10.20 (unresolved peak: 1H).

IR spectrum (KBr): 3100; 2931; 2644; 2543; 1609; 1581; 1507; 1482; 1456;1364; 1181; 1125; 1100; 1076; 761; 694 and 513 cm⁻¹.

The 3-difluoromethoxy-4-phenyl-1H-pyrazole can be prepared in thefollowing way:

A suspension of 2.55 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone,1.75 g of potassium carbonate and 1.82 g of methyl2-chloro-2,2-difluoroacetate in 40 cm³ of dimethylformamide is stirred,under an argon atmosphere, at ambient temperature for 16 hours and thenat a temperature of 65° C. for 8 hours. After cooling, 10 cm³ of a 10Nsodium hydroxide solution are added and the mixture is stirred for 1hour at ambient temperature, and then concentrated under reducedpressure (3 kPa). The residue is extracted with 200 cm³ of ethylacetate. The organic phase is washed with 3 times 25 cm³ of water, driedand concentrated under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on silica gel, eluting with amixture of dichloromethane and methanol (99/1 by volume). Afterconcentration of the fractions under reduced pressure, 0.8 g of3-difluoromethoxy-4-phenyl-1H-pyrazole is obtained in the form of ayellow solid which melts at 125° C. Mass spectrum (EI): m/z 210 (M^(+.))(base peak), m/z 160 [M-CF₂]^(+.).

EXAMPLE 22 4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylaminedihydrochloride

10 cm³ of 1N hydrochloric ether solution is added, in excess, to asolution of 0.2 g of4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine in 10 cm³ ofmethanol, and the mixture is concentrated to dryness under reducedpressure (3 kPa). The residue provides, after trituration in ethylether, 0.244 g of4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine dihydrochloridein the form of white crystals which melt at around 120° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.55 (mt:1H); from 1.60 to 1.90 (mt: 5H); 2.95 (unresolved peak: 2H); 3.44(unresolved peak: 2H); 3.51 (mt: 2H); 4.53 (t, J=6.5 Hz: 2H); 7.27(broad t, J=7.5 Hz: 1H); 7.42 (broad t, J=7.5 Hz: 2H); 7.56 (broad d,J=7.5 Hz: 2H); 8.07 (s: 1H); 10.46 (unresolved peak: 1H).

IR spectrum (KBr): 3277; 2945; 2630; 2545; 1612; 1540; 1451; 1099; 1005;768; 707; 572 and 559 cm⁻¹.

The 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine can beprepared in the following way:

A suspension of 1.59 g of 4-phenyl-1H-pyrazol-3-ylamine, 2.2 g of1-(2-chloroethyl)piperidine hydrochloride, 4 g of potassium carbonateand 1.66 g of potassium iodide in 50 cm³ of 2-butanone is stirred at theboiling temperature of the reaction medium for 22 hours. After cooling,the mixture is brought to dryness under reduced pressure (3 kPa). Theresidue is taken up with 40 cm³ of 0.5N sodium hydroxide solution andextracted with 50 cm³ of ethyl acetate. The organic phase is dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (3 kPa). The yellow oily residue is purified by chromatographyon basic alumina, eluting successively with a mixture of ethyl acetateand dichloromethane (50/50 by volume) and then with pure ethyl acetate.0.2 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine is thusobtained in the form of a white solid which melts at 96° C. and has anRf of 0.4 (ethyl acetate, aluminum oxide plate reference 105731, Merck).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 2H); 1.49(mt: 4H); 2.39 (broad t, J=5 Hz: 4H); 2.64 (t, J=6.5 Hz: 2H); 3.98 (t,J=6.5 Hz: 2H); 4.63 (s: 2H); 7.15 (tt, J=7.5 and 1.5 Hz: 1H); 7.34(broad t, J=7.5 Hz: 2H); 7.49 (broad d, J=7.5 Hz: 2H); 7.74 (s: 1H).

The 4-phenyl-1H-pyrazol-3-ylamine can be prepared according to themethod described by S. A. Lang, Jr. et al., J. Heterocyclic Chem. 1977,14, 65-69.

EXAMPLE 23 4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylaminedihydrochloride

2 cm³ of a 1M lithium aluminum hydride solution are added gradually, atambient temperature and under an argon atmosphere, to a solution of 0.25g of N-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-formamide in10 cm³ of anhydrous tetrahydrofuran. After stirring for 66 hours atambient temperature, 1 cm³ of 1N sodium hydroxide solution is addedgradually and the mixture is extracted with 20 cm³ of ethyl acetate.After removal of the gel by filtration, the organic phase isconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is purified by chromatography on basic alumina, eluting with amixture of dichloromethane and ethyl acetate (80/20 by volume). Afterconcentration of the fractions under reduced pressure, a colorless oilis obtained, which is dissolved in 10 cm³ of ethyl ether, and 1 cm³ ofan approximately 6N solution of hydrochloric dioxane is added, and themixture is then concentrated to dryness under reduced pressure (3 kPa).The residue is triturated in acetone and isolated by filtration. 0.045 gof 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylaminedihydrochloride is thus obtained in the form of a white solid whichmelts at around 165° C. (with decomposition).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50(unresolved peak: 1H); from 1.60 to 1.90 (mt: 5H); 1.6 (s: 3H); 2.94(unresolved peak: 2H); from 3.40 to 3.65 (mt: 4H); 4.42 (t, J=6.5 Hz:2H); 7.20 (broad t, J=7.5 Hz: 1H); 7.37 (broad t, J=7.5 Hz: 2H); 7.47(broad d, J=7.5 Hz: 2H); 7.89 (s: 1H); 9.93 (unresolved peak: 1H).

IR spectrum (KBr): 3289; 2943; 2600; 2534; 2481; 1627; 1530; 1446; 1342;1189; 850; 770; 706 and 499 cm⁻¹.

The N-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]formamide canbe prepared in the following way:

A solution of 0.24 g of4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine in 10 cm³ ofethyl formate is stirred at the boiling temperature of the reactionmedium for 23 hours. After cooling, the mixture is concentrated todryness under reduced pressure (3 kPa). 0.31 g ofN-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]formamide is thusobtained in the form of a colorless lacquer, which is used as it is inthe following step.

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, at a temperature of 373 K, δ inppm): 1.42 (mt: 2H); 1.52 (mt: 4H); 2.45 (t, J=5 Hz: 4H); 3.6 (t, J=6.5Hz: 2H); 4.17 (t, J=6.5 Hz: 2H); 7.24 (broad t, J=7.5 Hz: 1H); 7.38(broad t, J=7.5 Hz: 2H); 7.49 (broad d, J=7.5 Hz: 2H); 7.96 (s: 1H);8.30 (broad d, J=5 Hz: 1H); 9.49 (unresolved peak: 1H).

IR spectrum (KBr): 34434; 3218; 2955; 2799; 1683; 1631; 1607; 1325;1289; 765; 698 and 592 cm⁻¹.

EXAMPLE 24N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-acetamide oxalate

0.1 cm³ of acetic anhydride is added to a solution of 0.27 g of4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine in 5 cm³ ofchloroform, and the mixture is then stirred at ambient temperature for100 hours. After the mixture has been concentrated to dryness underreduced pressure (3 kPa), 15 cm³ of a saturated sodium hydrogencarbonate solution are added to the residue, which is extracted with 20cm³ of ethyl acetate. The organic phase is dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (3 kPa). Theoily residue obtained is dissolved in 10 cm³ of acetone and 0.1 g ofoxalic acid is added. The solution obtained is concentrated to drynessunder reduced pressure (3 kPa) and the residue is triturated in ethylether and isolated by filtration. 0.05 g ofN-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]acetamide oxalateis thus obtained in the form of a hygroscopic white solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.52 (mt: 2H); 1.70(mt: 4H); 2.01 (broad s: 3H); 3.01 (unresolved peak: 4H); 3.36 (broad t,J=6.5 Hz: 2H): 4.44 (broad t, J=6.5 Hz: 2H); 7.25 (broad t, J=7.5 Hz:1H); 7.38 (broad t, J=7.5 Hz: 2H); 7.47 (broad d, J=7.5 Hz: 2H); 8.11(broad s: 1H); 9.66 (unresolved peak: 1H).

IR spectrum (KBr): 3258; 3026; 2952; 2683; 2540; 1725; 1640; 1525; 1447;1373; 1202; 1008; 765 and 700 cm⁻¹.

EXAMPLE 25N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-methanesulfonamide

0.06 cm³ of methanesulfonyl chloride is added to a solution of 0.18 g of4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine in 5 cm³ ofchloroform, and the mixture is then stirred at ambient temperature for22 hours. 0.04 cm³ of methanesulfonyl chloride is added to the mixtureand the stirring is continued at ambient temperature for 3 hours. 15 cm³of a saturated sodium hydrogen carbonate solution are added to themixture, which is extracted with 25 cm³ of ethyl acetate. The organicphase is dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (3 kPa). The oily residue obtained ispurified by chromatography on basic alumina, eluting successively withpure ethyl acetate and then with a mixture of ethyl acetate and methanol(30/1 by volume). After concentration of the fractions under reducedpressure, a colorless residue is obtained, which is crystallized bytrituration from ethyl ether and isolated by filtration. 0.05 g ofN-[4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]-methanesulfonamideis thus obtained in the form of a white solid which melts at 121° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.40 to 1.55 (mt:6H); 2.41 (broad t, J=5 Hz: 4H); 3.1 (t, J=6.5 Hz: 2H); 3.11 (s: 3H);4.18 (t, J=6.5 Hz: 2H); 7.23 (broad t, J=7.5 Hz: 1H); 7.38 (broad t,J=7.5 Hz: 2H); 7.69 (broad d, J=7.5 Hz: 2H); 8.06 (s: 1H); from 9.00 to9.70 (very broad unresolved peak: 1H).

IR spectrum (KBr): 3105; 2928; 1610; 1440; 1321; 1149; 976; 765; 699;524 and 518 cm¹.

EXAMPLE 26 1-(2-Dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-oldihydrochloride

1 cm³ of a 4N hydrochloric solution in dioxane is added gradually, at atemperature in the region of 20° C., to a solution of 0.42 g of{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethylaminein 5 cm³ of methanol, with stirring. After stirring for 15 hours at atemperature in the region of 20° C., the reaction mixture isconcentrated to dryness under reduced pressure (2.7 kPa) and dried at40° C. under reduced pressure (2.7 kPa) so as to give 0.37 g of1-(2-dimethylaminopropyl)-4-phenyl-1H-pyrazol-3-ol dihydrochloride inthe form of a white solid which melts at 189° C. Mass spectrum (CI): m/z246 (MH⁺) base peak.

The{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethylaminecan be prepared in the following way:

A solution of 1 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole in 5cm³ of dimethylformamide is added to a suspension, which is stirredunder an argon atmosphere, of 1.3 g of sodium hydride (at 75% in liquidpetroleum jelly) in 5 cm³ of dimethylformamide. After stirring for 15minutes at a temperature in the region of 20° C., and then for 30minutes at 50° C., the reaction medium is cooled to a temperature in theregion of 20° C., and 1.3 g of (2-chloro-1-methylethyl)dimethylaminehydrochloride are added with stirring, and the mixture is then broughtto 50° C. for 15 hours. After the addition of a further 0.14 g of sodiumhydride (at 75% in liquid petroleum jelly) and a further 0.7 g of(2-chloro-1-methylethyl)dimethylamine hydrochloride, the reaction iscontinued for 15 hours at 50° C., and the reaction medium is then cooledto a temperature in the region of 20° C. and concentrated to drynessunder reduced pressure (2.7 kPa). The residue obtained is taken up in100 cm³ of water; the resulting aqueous phase is extracted with 3 times30 cm³ of dichloromethane, and the organic phase is dried over magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).1.2 g of a brown oil is obtained, which is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent:dichloromethane/methanol (95/5 by volume)]. After concentration of thefractions to dryness under reduced pressure (2.7 kPa), 0.42 g of{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}dimethylamineis obtained in the form of an oil [TLC: eluent: dichloromethane/methanol(95/5 by volume), Rf=0.13].

Mass spectrum (EI): m/z 325 (M^(+.)), m/z 72 (C₄H₁₀N^(+.)).

The 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole can be prepared in thefollowing way:

2.02 g of 1-(3-hydroxy-4-phenylpyrazol-1-yl)ethanone, 1.27 cm³ of3-bromocyclohexene and 1.52 g of potassium carbonate are added to 20 cm³of methyl ethyl ketone with stirring at a temperature in the region of20° C. After heating for 3 hours at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is taken up in a mixture of 20 cm³ of tetrahydrofuran and 20cm³ of methanol, and 2 cm³ of 5N sodium hydroxide are then added theretowith stirring. After stirring for 30 minutes at a temperature in theregion of 20° C., the reaction medium is concentrated to dryness underreduced pressure (2.7 kPa), which results in a residue which issolubilized in 100 cm³ of ethyl acetate. The organic solution is washedwith two times 20 cm³ of water and with 20 cm³ of water saturated withsodium chloride, dried over magnesium sulfate, filtered, and evaporatedto dryness under reduced pressure (2.7 kPa). The solid obtained is takenup with 5 cm³ of ethyl acetate under hot conditions with stirring; 40cm³ of diisopropyl ether are added to the solution, which is brought tothe reflux of the solvent for 15 minutes and then cooled to atemperature in the region of 20° C. A first crystallization crop isfiltered off, washed with 10 cm³ of diisopropyl ether and 10 cm³ ofpentane, and dried under reduced pressure (2.7 kPa) to give 1.07 g of3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole in the form of a whitepowder. The crystallization filtrate is evaporated to dryness underreduced pressure (2.7 kPa) and taken up with 20 cm³ of diisopropylether, and 20 cm³ of pentane are added; a second crystallization crop isfiltered off and dried under reduced pressure (2.7 kPa), to give 0.33 gof a batch which is identical to the preceding one [TLC: eluent:cyclohexane/ethyl acetate (70/30 by volume), Rf=0.23]. Mass spectrum(EI): m/z 240 (M^(+.)), m/z 160 [(M-C₆H₈)^(+.)].

EXAMPLE 27 1-(1-Methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol

0.86 g of 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidine,0.1 g of palladium-on-charcoal at 10%, 10 cm³ of cyclohexene and 20 cm³of ethanol are added to 20 cm³ of ethanol at a temperature in the regionof 20° C. After 15 hours at 50° C., 0.1 g of palladium-on-charcoal at10% and 10 cm³ of cyclohexene are added to the reaction medium; themixture is brought to the reflux of the solvent for 1 hour, and afurther 15 cm³ of cyclohexene are then added and the reaction iscontinued at the reflux of the solvent for 5 hours. The catalyst isfiltered off over supercel, and the solution is evaporated to drynessunder reduced pressure (2.7 kPa) to give 0.48 g of a solid which istriturated in 10 cm³ of a mixture of diisopropyl ether and pentane.After filtration, 0.3 g of a solid is obtained, which is used again inreaction with 10 cm³ of ethanol, 10 cm³ of cyclohexene and 0.1 g ofpalladium-on-charcoal at 10% with stirring and at the reflux of thesolvent for 15 hours. The catalyst is filtered off over supercel, andthe filtrate is evaporated to dryness under reduced pressure (2.7 kPa)to give 0.3 g of a solid which is purified by flash chromatography onsilica under an argon pressure (50 kPa) [eluent:dichloromethane/methanol/38% aqueous ammonia solution (88/10/2 byvolume)]. After concentration of the fractions under reduced pressure(2.7 kPa), 0.15 g of a yellowish solid is obtained, which is taken up in70 cm³ of methanol at a temperature in the region of 20° C. 1 cm³ of 4Nhydrochloric acid in dioxane is added to the solution, which is stirredfor 15 minutes at a temperature in the region of 20° C. and is thenevaporated to dryness under reduced pressure (2.7 kPa) to give 0.19 g ofa foam which is triturated in diisopropyl ether and filtered. Thedeliquescent solid is taken up with 1 cm³ of 1N sodium hydroxide, andthe aqueous phase is washed with dichloromethane, partially evaporatedunder reduced pressure (2.7 kPa), adjusted to pH 8 by adding 0.1Nhydrochloric acid, and extracting with dichloromethane. The organicphase is dried over magnesium sulfate, filtered and evaporated underreduced pressure (2.7 kPa) to give 0.15 g of1-(1-methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol in the form ofa cream foam which melts at 132° C.

Mass spectrum (ES): m/z 272 (MH⁺).

The 3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidine can beprepared in the following way:

0.4 g of sodium hydride (at 75% in liquid petroleum jelly) is addedgradually, at a temperature in the region of 20° C., to a solution of 1g of 3-benzyloxy-4-phenyl-1H-pyrazole in 10 cm³ of dimethylformamideunder an argon atmosphere and with stirring, and the mixture is thenbrought to 50° C. for 10 minutes. After the addition of 1.5 g of3-chloromethyl-1-methylpiperidine hydrochloride, the reaction medium isheated at 80° C. for 15 hours, and is then cooled to a temperature inthe region of 20° C. and poured into 100 cm³ of water. The mixture isextracted with dichloromethane; the organic phase is dried overmagnesium sulfate, filtered and evaporated to dryness under reducedpressure (2.7 kPa) to give 1.6 g of a brown oil which is purified byflash chromatography on silica under an argon pressure (50 kPa) [eluent:dichloromethane/methanol (95/5 by volume)]. After concentration of thefractions to dryness under reduced pressure (2.7 kPa), 0.86 g of3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-methylpiperidine isobtained in the form of a yellow oil [TLC: eluent:dichloromethane/methanol/38% aqueous ammonia solution (88/10/2 byvolume), Rf=0.41]. Mass spectrum (EI): m/z 361 (M^(+.)), m/z 270[(M-C₇H₇)^(+.)].

EXAMPLE 28 5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

1.5 cm³ of a 4N hydrochloric solution in dioxane are added gradually,with stirring, at a temperature in the region of 20° C., to a solutionof 0.3 g of1-{2-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]-ethyl}piperidinein 10 cm³ of methanol. After stirring for 15 hours at a temperature inthe region of 20° C., the reaction mixture is concentrated to drynessunder reduced pressure (2.7 kPa). The residue is triturated indiisopropyl ether, filtered, and dried under reduced pressure (2.7 kPa)at 40° C. for 2 hours to give 0.19 g of5-methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a cream solid which melts at 222° C. Massspectrum (CI): m/z 286 (MH⁺).

The1-{2-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethyl}piperidinecan be prepared in the following way:

0.2 g of sodium hydride at 75% in liquid petroleum jelly is addedgradually, at a temperature in the region of 20° C., to a solution of0.46 g of 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole in 15 cm³of dimethylformamide with stirring and under an argon atmosphere. Afterheating for 5 minutes at 50° C., 0.67 g of 1-(2-chloroethyl)piperidinehydrochloride is added to the reaction medium, and the solution is thenheated at 80° C. for 15 hours. The reaction medium is poured into 100cm³ of water; the aqueous phase is extracted with dichloromethane, whichis dried over magnesium sulfate and concentrated to dryness underreduced pressure (2.7 kPa). The resulting brown oil (0.8 g) is purifiedby flash chromatography on silica under an argon pressure (50 kPa)[eluent: dichloromethane/methanol (95/5 by volume)]. After concentrationof the fractions to dryness under reduced pressure (2.7 kPa), 0.3 g of3-(cyclohex-2-en-1-yloxy)-5-methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazoleis obtained in the form of a yellow oil [TLC: eluent:dichloromethane/methanol (90/10 by volume), Rf=0.27].

Mass spectrum (CI): m/z 366 (MH⁺).

The 3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole can be preparedin the following way:

0.54 cm³ of 5N sodium hydroxide is added gradually, at a temperature inthe region of 20° C., to a solution, with stirring, of 0.8 g of1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone in amixture of 20 cm³ of methanol and 20 cm³ of tetrahydrofuran. Afterstirring for 6 hours at a temperature in the region of 20° C., thereaction mixture is concentrated to dryness under reduced pressure (2.7kPa), and the residue is taken up with 100 cm³ of dichloromethane and 10cm³ of water; the organic phase is separated by settling out, dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) to give 0.46 g of3-(cyclohex-2-enyloxy)-5-methyl-4-phenyl-1H-pyrazole in the form of ayellow gum [TLC: eluent: cyclohexane/ethyl acetate (70/30 by volume),Rf=0.19]. Mass spectrum (EI): m/z (254 M^(+.)), m/z 174 [(M-C₆H₈)^(+.)].

The 1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone canbe prepared in the following way:

2 g of 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone, 1.3 g ofpotassium carbonate and 1.06 cm³ of 3-bromocyclohexene are added to 100cm³ of methyl ethyl ketone at 20° C. with stirring. After heating at thereflux of the solvent for 5 hours, the reaction medium is cooled to atemperature in the region of 20° C. and then concentrated to drynessunder reduced pressure (2.7 kPa). The residue is taken up with 100 cm³of water and 100 cm³ of dichloromethane; the organic phase is separatedby settling out, dried over magnesium sulfate, filtered and concentratedto dryness under reduced pressure (2.7 kPa). The resulting brown oil(2.7 g) is purified by flash chromatography on silica [eluent:cyclohexane/ethyl acetate (70/30 by volume)]. After concentration of thefractions to dryness under reduced pressure (2.7 kPa), 0.8 g of1-[3-(cyclohex-2-enyloxy)-5-methyl-4-phenylpyrazol-1-yl]ethanone isobtained in the form of a yellow oil [TLC: eluent: cyclohexane/ethylacetate (70/30 by volume), Rf=0.74]. Mass spectrum (EI): m/z 296(M^(+.)), m/z 174 [(216-C₂H₂O)^(+.)].

The 1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone can be preparedin the following way:

0.85 cm³ of acetic anhydride is added to a solution of 1.74 g of5-methyl-4-phenyl-1H-pyrazol-3-ol (CAS No.: 64754-67-2) in 17 cm³ ofpyridine with stirring and which has been brought to 100° C. Afterheating at this temperature for 30 minutes, the reaction medium iscooled to a temperature in the region of 20° C. and is then poured into100 cm³ of a mixture of ice and water. The solution is extracted with 2times 50 cm³ of ethyl acetate; the organic phases are pooled, washedwith twice 100 cm³ of water, dried over magnesium sulfate, filtered andevaporated to dryness under reduced pressure (2.7 kPa); 2 g of1-(3-hydroxy-5-methyl-4-phenylpyrazol-1-yl)ethanone are obtained in theform of an orange-yellow oil. Mass spectrum (EI): m/z 216 (M^(+.)), m/z174 [(M-C₂H₂O)^(+.)].

EXAMPLE 29 4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-oltrihydrochloride

A solution of 500 mg of{2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-yl]ethyl}dimethylamine in 15cm³ of methanol is added to a mixture of 860 mg of ammonium formate andof 50 mg of palladium hydroxide at 10% in 15 cm³ of methanol, and thismixture is heated for 3 hours at the reflux of the solvent withstirring. The reaction medium is then filtered over supercel, and thefiltrate is evaporated under reduced pressure (2.7 kPa). The reactioncrude is taken up with dichloromethane and the resulting mixture iswashed successively with a saturated aqueous hydrogen carbonatesolution, water and a saturated aqueous sodium chloride solution. Theaqueous phases are pooled and evaporated under reduced pressure (2.7kPa). The residue obtained is taken up with methanol and the suspensionis filtered. After evaporation of the filtrate under reduced pressure(2.7 kPa), the residual solid is triturated in 3N hydrochloric ethanol.The precipitate formed is filtered off and dried under vacuum (2.7 kPa)to give 110 mg of4-(3-aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-oltrihydrochloride in the form of a beige solid.

IR spectrum (KBr): 3432; 2839; 2689; 2586; 1627; 1603; 1523; 1462; 1178;786 and 696 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.80 (s: 6H); 3.45 (t,J=6.5 Hz: 2H); 4.41 (t, J=6.5 Hz: 2H); 7.10 (broad d, J=8 Hz: 1H); 7.42(t, J=8 Hz: 1H); 7.58 (broad d, J=8 Hz: 1H); 7.67 (broad s: 1H); 8.10(s: 1H); from 9.50 to 10.40 (very broad unresolved peak: 1H); 10.50(unresolved peak: 1H); 10.73 (unresolved peak: 1H).

The {2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-yl]-ethyl}dimethylaminecan be prepared in the following way:

A solution of 3.45 g of 3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole in 50cm³ of dimethylformamide is added to a suspension of 1.13 g of sodiumhydride (at 75% in liquid petroleum jelly) in 50 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 minutes, the mixture is stirred for 1 h at atemperature in the region of 20° C. and is then cooled in an ice bathand a solution of 4.5 g of (2-bromoethyl)dimethylamine hydrobromide in50 cm³ of dimethylformamide is added. The reaction mixture is stirredfor 15 h at a temperature in the region of 20° C., and 1.5 h at 50° C.,and is then cooled to a temperature in the region of 20° C. and pouredinto 400 cm³ of water. The aqueous phase is extracted twice with ethylacetate. The organic phases are pooled, washed successively with waterand a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa) togive an orange-colored oil which is purified by flash chromatography onsilica under an argon pressure (50 kPa) [eluent: ethyl acetate, thenethyl acetate/methanol (90/10 by volume)]. After concentration of thefractions under reduced pressure, 1.7 g of{2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-yl]ethyl}dimethylamine areobtained in the form of an orange-colored oil. Mass spectrum (EI): m/z366 (M^(+.)), m/z 91 (C₇H₇ ⁺), m/z 71 (C₄H₉N^(+.)), m/z 58 (C₃H₈N⁺).

The 3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole can be prepared in thefollowing way:

2.75 g of potassium carbonate and 2.2 cm³ of benzyl bromide are added toa suspension of 4.1 g of1-[3-hydroxy-4-(3-nitrophenyl)pyrazol-1-yl]ethanone in 50 cm³ of methylethyl ketone with stirring. The mixture is heated at the reflux of thesolvent for 2.5 h, cooled to a temperature in the region of 20° C., andfiltered. The filtrate is evaporated under reduced pressure (2.7 kPa)and the residue is taken up with 25 cm³ of tetrahydrofuran and 25 cm³ ofmethanol and 1 cm³ of 10N sodium hydroxide is added thereto. Afterstirring for 30 min at a temperature in the region of 20° C., thereaction medium is evaporated under reduced pressure (2.7 kPa). Thereaction crude is taken up in dichloromethane. The organic phase iswashed successively with water and a saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and evaporated underreduced pressure (2.7 kPa) to give an oil which is triturated indiisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 3.47 g of3-benzyloxy-4-(3-nitrophenyl)-1H-pyrazole in the form of a yellow solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.40 (s: 2H); 7.36(broad t, J=7.5 Hz: 1H); 7.44 (broad t, J=7.5 Hz: 2H); 7.55 (broad d,J=7.5 Hz: 2H); 7.64 (t, J=8 Hz: 1H); 8.00 (dd, J=8 and 2 Hz: 1H); 8.13(broad d, J=8 Hz: 1H); 8.33 (s: 1H); 8.62 (t, J=2 Hz: 1H); from 12.00 to12.80 (very broad unresolved peak: 1H).

The 1-[3-hydroxy-4-(3-nitrophenyl)pyrazol-1-yl]ethanone can be preparedin the following way:

A solution of 3.8 g of dimethylammonium4-(3-nitrophenyl)-1H-pyrazol-3-olate in 40 cm³ of pyridine, under anargon atmosphere and with stirring, is heated to 90° C. and 1.5 cm³ ofacetic anhydride are then added dropwise. After heating for 1 h at 90°C., the reaction medium is cooled to a temperature in the region of 20°C. and is poured into 100 cm³ of ice-cold water. The precipitate formedis filtered, washed 3 times with water and dried under vacuum (2.7 kPa)to give 4.33 g of a solid which is used again in reaction with 40 cm³ ofpyridine and 0.39 cm³ of acetic anhydride according to the protocolstated above. 4.1 g of1-[3-hydroxy-4-(3-nitrophenyl)pyrazol-1-yl]ethanone are obtained in theform of a pale yellow solid. IR spectrum (KBr): 3118; 3082; 2669; 1730;1604; 1520; 1390; 1349; 1256; 1223; 1101; 748 and 719 cm⁻¹.

The dimethylammonium 4-(3-nitrophenyl)-1H-pyrazol-3-olate can beprepared in the following way:

A solution, with stirring, of 9.3 g of benzyl ester of3-dimethylamino-2-(3-nitrophenyl)acrylic acid and 1.4 cm³ of hydrazinemonohydrate in 100 cm³ of ethanol is heated for 3 h at the reflux of thesolvent, and then cooled in an ice bath. The solid formed is filteredoff, washed with water, and dried under vacuum (2.7 kPa) to give 4.44 gof dimethylammonium 4-(3-nitrophenyl)-1H-pyrazol-3-olate in the form ofan orange-colored solid.

IR spectrum (KBr): 3346; 3199; 3071; 2855; 2685; 2386; 1583; 1538; 1469;1350; 934; 766; 747 and 681 cm⁻¹.

The benzyl ester of 3-dimethylamino-2-(3-nitrophenyl)-acrylic acid canbe prepared in the following way:

11.5 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine is addedto a solution of 10 g of benzyl ester of 2-(3-nitrophenyl)acrylic acidin 100 cm³ of tetrahydrofuran and the mixture is heated for 15 h at thereflux of the solvent. After cooling to a temperature in the region of20° C., the reaction mixture is evaporated to dryness under reducedpressure (2.7 kPa). The residue is taken up with ethyl acetate and theorganic solution is washed 3 times with water and then with a saturatedaqueous sodium chloride solution, dried over magnesium sulfate, filteredand evaporated under reduced pressure (2.7 kPa). The brown oil obtainedis purified by flash chromatography on silica under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Afterconcentration of the fractions under reduced pressure, 9.3 g of benzylester of 3-dimethylamino-2-(3-nitrophenyl)acrylic acid are obtained inthe form of an orange-colored oil. Mass spectrum (EI): m/z 326 (M^(+.)),m/z 235 [(M-C₇H₇)⁺], m/z 91 (C₇H₇ ⁺).

EXAMPLE 30N-{3-[3-Hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamidedihydrochloride

1.8 cm³ of 3N hydrochloric diethyl ether are added to a solution of 400mg ofN-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamidein 20 cm³ of ethanol. After stirring for 15 min at a temperature in theregion of 20° C., the solution is evaporated to dryness under reducedpressure (2.7 kPa). The residue is taken up in 20 cm³ of ethanol. Thesolution obtained is introduced into an autoclave, and 50 mg ofpalladium-on-charcoal at 10% are added, and it is then placed underhydrogen (5 bar). After stirring for 2 h at a temperature in the regionof 20° C., the reaction medium is filtered over supercel and thefiltrate is evaporated. The yellow oil obtained (440 mg) is dissolved in20 cm³ of ethanol and used again in reaction with 50 mg ofpalladium-on-charcoal at 10%, under hydrogen (5 bar), at 40° C. and withstirring for 4 h. The reaction medium is then filtered over supercel,the filtrate is evaporated, and the residue is triturated in diisopropylether. The precipitate formed is filtered, and dried under vacuum (2.7kPa) to give 289 mg ofN-{3-[3-hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamidedihydrochloride in the form of a pale yellow solid.

IR spectrum (KBr): 3242; 3130; 2967; 2573; 2464; 1678; 1614; 1588; 1525;1462; 1258; 1187; 787 and 690 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.05 (s: 3H); 2.80(broad s: 6H); 3.48 (broad t, J=6.5 Hz: 2H); 4.35 (broad t, J=6.5 Hz:2H); 7.23 (t, J=7.5 Hz: 1H); 7.31 (broad d, J=7.5 Hz: 1H); 7.38 (broadd, J=7.5 Hz: 1H); 7.89 (broad s: 1H); 7.95 (s: 1H); from 9.60 to 9.85(broad unresolved peak: 1H); 9.91 (broad s: 1H); 10.45 (broad s: 1H).

TheN-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamidecan be prepared in the following way:

0.116 cm³ of acetyl chloride is added to a solution of 500 mg of3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenylamine and0.418 cm³ of triethylamine in 20 cm³ of dichloromethane under an argonatmosphere and with stirring, while maintaining the temperature of themedium at 5° C. After stirring for 15 h at a temperature in the regionof 20° C., a further 0.1 cm³ of triethylamine and 0.1 cm³ of acetylchloride are added to the reaction mixture and the reaction is continuedfor 2 h. The reaction medium is then washed successively twice withwater and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give 540 mg ofN-{3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamidein the form of a yellow oil.

IR spectrum (CCl₄): 3444; 3305; 2945; 2822; 2773; 1670; 1614; 1588;1549; 1502; 1452; 1423; 1357; 1177; 1018; 695 and 537 cm⁻¹.

The 3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenylaminecan be prepared in the following way:

A solution of 1.1 g of{2-[3-benzyloxy-4-(3-nitrophenyl)pyrazol-1-yl]ethyl}dimethylamine in 15cm³ of ethanol is added to a mixture, with stirring, of 840 mg of ironpowder, 200 mg of ammonium chloride in 15 cm³ of ethanol and 15 cm³ ofwater, heated at the reflux of the solvent. The stirring is continuedfor 3 h at the reflux of the solvent and then for 15 h at a temperaturein the region of 20° C. The reaction mixture is filtered and thefiltrate is evaporated. The residue is taken up with a mixture of ethylacetate, water and 1N sodium hydroxide. The organic phase is separatedby settling out, washed successively with water and a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa) to give 1 g of3-[3-benzyloxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenylamine inthe form of an orange-colored oil.

Mass spectrum (EI): m/z 336 (M^(+.)), m/z 265 [(M-C₇H₇)⁺], m/z 91 (C₇H₇⁺), m/z 71 (C₄H₉N^(+.)), m/z 58 (C₃H₈N⁺).

EXAMPLE 31 4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-oldihydrochloride

1.2 cm³ of 3N hydrochloric diethyl ether are added to a solution of 250mg of {2-[3-benzyloxy-4-(4-nitrophenyl)pyrazol-1-yl]ethyl}dimethylaminein 20 cm³ of ethanol. After stirring for 20 minutes at a temperature inthe region of 20° C., the solution is evaporated to dryness underreduced pressure (2.7 kPa). The residue is taken up with 20 cm³ ofethanol. The solution obtained is introduced into an autoclave and 36 mgof palladium-on-charcoal at 10% are added, and it is then placed underhydrogen (7 bar). After stirring for 5 h at 40° C., the reaction mediumis filtered over supercel, the filtrate is evaporated and the residue istriturated in diisopropyl ether. The precipitate formed is filtered, anddried under vacuum (2.7 kPa) to give 169 mg of4-(4-aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-oldihydrochloride in the form of a yellow solid.

IR spectrum (KBr): 3372; 3296; 3205; 3025; 1627; 1592, 1522; 1514; 1451;1280; 1177; 828; 612 and 525 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.75 (s: 6H); 3.42(mt: 2H); 4.27 (t, J=6 Hz: 2H); from 4.70 to 5.30 (broad unresolvedpeak: 2H); 6.55 (d, J=8.5 Hz: 2H); 7.31 (d, J=8.5 Hz: 2H); 7.75 (s: 1H);10.08 (unresolved peak: 1H).

The {2-[3-benzyloxy-4-(4-nitrophenyl)pyrazol-1-yl]-ethyl}dimethylaminecan be prepared in the following way:

A solution of 3 g of 3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole in 50 cm³of dimethylformamide is added to a suspension of 980 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 50 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating for 30 min at 50° C., the mixture is stirred for 1 h at atemperature in the region of 20° C. and is then cooled in an ice bathand a solution of 4.7 g of (2-bromoethyl)dimethylamine hydrobromide in50 cm³ of dimethylformamide is added. The reaction medium is stirred for15 h at a temperature in the region of 20° C. and is then poured into400 cm³ of water. The aqueous phase is extracted twice with ethylacetate. The organic phases are pooled, washed successively with watertwice and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give an orange-colored oil which is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent: ethylacetate, then ethyl acetate/methanol (90/10 by volume)]. Afterconcentration of the fractions under reduced pressure, 1.2 g{2-[3-benzyloxy-4-(4-nitrophenyl)pyrazol-1-yl]-ethyl}dimethylamine areobtained in the form of a brown oil. Mass spectrum (EI): m/z 366(M^(+.)), m/z 91 (C₇H₇ ⁺), m/z 71 (C₄H₉N^(+.)), m/z 58 (C₃H₈N⁺).

The 3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole can be prepared in thefollowing way:

3 g of potassium carbonate and 2.2 cm³ of benzyl bromide are added to asuspension of 4.5 g of1-[3-hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]ethanone in 50 cm³ of methylethyl ketone with stirring. The mixture is heated at the reflux of thesolvent for 2.5 h, cooled to a temperature in the region of 20° C., andfiltered. The filtrate is evaporated under reduced pressure (2.7 kPa)and the residue is taken up with 25 cm³ of tetrahydrofuran and 25 cm³ ofmethanol, and 2 cm³ of 10N sodium hydroxide are then added. Afterstirring for 30 min at a temperature in the region of 20° C., thereaction medium is evaporated under reduced pressure (2.7 kPa). Thereaction crude is taken up in dichloromethane. The organic phase iswashed successively with water and a saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and evaporated underreduced pressure (2.7 kPa) to give an oil which is triturated indiisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 3 g of3-benzyloxy-4-(4-nitrophenyl)-1H-pyrazole in the form of an ochre solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.41 (s: 2H); from7.30 to 7.60 (mt: 5H); 7.97 (d, J=9 Hz: 2H); 8.23 (d, J=9 Hz: 2H); 8.36(s: 1H); 12.49 (unresolved peak: 1H).

The 1-[3-hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]-ethanone can be preparedin the following way:

A solution of 4.85 g of dimethylammonium4-(4-nitrophenyl)-1H-pyrazol-3-olate in 40 cm³ of pyridine, under anargon atmosphere and with stirring, is heated to 90° C. and 2 cm³ ofacetic anhydride are then added dropwise. After heating for 1 h at 90°C., the reaction medium is cooled to a temperature in the region of 20°C. and is poured into 100 cm³ of ice-cold water. The precipitate formedis filtered, washed three times with water, and dried under vacuum (2.7kPa) to give 4.5 g of1-[3-hydroxy-4-(4-nitrophenyl)pyrazol-1-yl]ethanone in the form of ayellow solid.

IR spectrum (KBr): 3370; 3128; 2980; 2587; 1721; 1615; 1600; 1509; 1341;1224; 1111; 855; 757 and 643 cm⁻¹.

The dimethylammonium 4-(4-nitrophenyl)-1H-pyrazol-3-olate can beprepared in the following way:

A solution, with stirring, of 10.7 g of methyl ester of3-dimethylamino-2-(4-nitrophenyl)acrylic acid and of 2.1 cm³ ofhydrazine monohydrate in 120 cm³ of ethanol is heated for 3 h at thereflux of the solvent, and cooled in an ice bath. The solid formed isfiltered, rinsed with diisopropyl ether, and dried under vacuum (2.7kPa) to give 5 g of dimethylammonium4-(4-nitrophenyl)-1H-pyrazol-3-olate in the form of an orange-coloredsolid.

IR spectrum (KBr): 3188; 3089; 2909; 2728; 2423; 1603; 1589; 1567; 1538;1501; 1345; 1330; 1212; 1112; 923; 880; 761 and 581 cm⁻¹.

The methyl ester of 3-dimethylamino-2-(4-nitrophenyl)-acrylic acid canbe prepared in the following way:

16.6 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine are addedto a solution of 10.5 g of methyl ester of 2-(4-nitrophenyl)acrylic acidin 100 cm³ of tetrahydrofuran, and the mixture is heated for 2.5 h atthe reflux of the solvent. After stirring for 15 h at a temperature inthe region of 20° C., the reaction mixture is evaporated to drynessunder reduced pressure (2.7 kPa). The residue is taken up with ethylacetate and the organic solution is washed with three times water, andthen dried over magnesium sulfate, filtered and evaporated under reducedpressure (2.7 kPa) to give 10.7 g of methyl ester of3-dimethylamino-2-(4-nitrophenyl)acrylic acid in the form of a brownoil.

IR spectrum (CCl₄): 2949; 1693; 1603; 1519; 1433; 1344; 1219; 1995; 1048and 855 cm⁻¹.

EXAMPLE 321-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-3-yl)-1H-pyrazol-3-oldihydrochloride

1.2 cm³ of 3N hydrochloric diethyl ether are added to a solution of 300mg of{2-[3-benzyloxy-4-(4′-fluorobiphenyl-3-yl)pyrazol-1-yl]ethyl}dimethylaminein 20 cm³ of ethanol. After stirring for 30 min at a temperature in theregion of 20° C., the solution is evaporated to dryness under reducedpressure (2.7 kPa). The residue is taken up with 20 cm³ of ethanol. Thesolution obtained is introduced into an autoclave and 14 mg ofpalladium-on-charcoal at 10% are added, and it is then placed underhydrogen (7 bar). After stirring for 5 h at 30° C., the reaction mediumis filtered over supercel, and the filtrate is evaporated. Diisopropylether is added to the residue, resulting in a suspension, which isheated at the reflux of the solvent and filtered under hot conditions.The resulting solid is dried under vacuum (2.7 kPa) to give 84 mg of1-(2-dimethylaminoethyl)-4-(4′-fluorobiphenyl-3-yl)-1H-pyrazol-3-oldihydrochloride in the form of a white powder.

IR spectrum (KBr): 3049; 2962; 2682; 2355; 1608; 1514; 1460; 1221; 1184;1162; 843; 804; 703 and 560 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.76 (broad s: 6H);3,45 (mt: 2H); 4.32 (broad t, J=6 Hz: 2H); 7.32 (t, J=8.5 Hz: 2H); from7.35 to 7.50 (mt: 2H); 7.66 (mt: 1H); 7.70 (dd, J=9 and 6 Hz: 2H); 7.90(broad s: 1H); 8.14 (s: 1H); 9.76 (unresolved peak: 1H); 10.50 (broad s:1H).

The{2-[3-benzyloxy-4-(4′-fluorobiphenyl-3-yl)pyrazol-1-yl]ethyl}dimethylaminecan be prepared in the following way:

860 mg of 4-fluorophenylboronic acid, 1.3 g of potassium phosphate and330 mg of bis(triphenylphosphine)palladium chloride are added to astirred solution of 620 mg of{2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethyl}dimethylamine in 25cm³ of toluene under an argon atmosphere. After heating at the reflux ofthe solvent for 15 h, the reaction medium is cooled to a temperature inthe region of 20° C., ethyl acetate and water are added, and the mixtureis filtered over supercel. The filtrate is separated by settling out andthe organic phase is then washed successively with 0.5N sodiumhydroxide, water and a saturated aqueous sodium chloride solution; it isdried over magnesium sulfate, filtered and evaporated under reducedpressure (2.7 kPa). The brown oil obtained (1.3 g) is purified by flashchromatography on alumina CRB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (80/20 by volume)]. After concentration of thefractions under reduced pressure, 300 mg of{2-[3-benzyloxy-4-(4′-fluorobiphenyl-3-yl)-pyrazol-1-yl]ethyl}dimethylamineare obtained in the form of a yellow oil.

IR spectrum (CCl4): 2823; 2773; 1610; 1571; 1515; 1462; 1358; 1235;1158; 1014; 837; 696 and 559 cm⁻¹.

The {2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]-ethyl}dimethylaminecan be prepared in the following way:

A solution of 7.67 g of 3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole in 70cm³ of dimethylformamide is added to a suspension of 2.25 g of sodiumhydride (at 75% in liquid petroleum jelly) in 70 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating for 30 min at 50° C., the mixture is stirred for 1 h at atemperature in the region of 20° C. and is then cooled in an ice bathand a solution of 10.85 g of (2-bromoethyl)dimethylamine hydrobromide in100 cm³ of dimethylformamide is added. The reaction medium is stirredfor 15 h at a temperature in the region of 20° C., and for 3 h at 50°C., and is then cooled to a temperature in the region of 20° C. andpoured into 500 cm³ of water. The aqueous phase is extracted twice withethyl acetate. The organic phases are pooled, washed successively withwater twice and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give an orange-colored oil which is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent: ethylacetate, ethyl acetate/methanol (90/10 by volume)]. After concentrationof the fractions under reduced pressure, 2.4 g of{2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethyl}dimethylamine areobtained in the form of an orange-colored oil.

Mass spectrum (CI): m/z 400 (MH⁺), m/z 322 [(M-Br+2H)⁺].

The 3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole can be prepared in thefollowing way:

2.6 g of potassium carbonate and 2.05 cm³ of benzyl bromide are added toa suspension of 4.4 g of1-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethanone in 50 cm³ ofmethyl ethyl ketone with stirring. The mixture is heated at the refluxof the solvent for 2.5 h, cooled to a temperature in the region of 20°C., and filtered. The filtrate is evaporated under reduced pressure (2.7kPa), and the residue is taken up with 25 cm³ of tetrahydrofuran and 25cm³ of methanol, and 1 cm³ of 10N sodium hydroxide is then added. Afterstirring for 30 min at a temperature in the region of 20° C., thereaction medium is evaporated under reduced pressure (2.7 kPa). Thereaction crude is taken up in dichloromethane. The organic phase iswashed successively with water twice and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa) to give an oil which is purified byflash chromatography on silica under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (80/20 by volume)]. After concentration of thefractions under reduced pressure, 3.3 g of3-benzyloxy-4-(3-bromophenyl)-1H-pyrazole are obtained in the form of acream solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.35 (s: 2H); from7.25 to 7.40 (mt: 3H); 7.42 (broad t, J=7.5 Hz: 2H); 7.51 (broad d,J=7.5 Hz: 2H); 7.71 (dt, J=7.5 and 2 Hz: 1H); 7.93 (broad s: 1H); 8.18(s: 1H); 12.25 (unresolved peak: 1H).

The 1-[4-(3-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone can be preparedin the following way:

A solution of 4.3 g of 4-(3-bromophenyl)-1H-pyrazol-3-ol in 40 cm³ ofpyridine, under an argon atmosphere and with stirring, is heated to 90°C. and 1.6 cm³ of acetic anhydride are then added dropwise. Afterheating for 1 h at 90° C., the reaction medium is cooled to atemperature in the region of 20° C. and is poured into 100 cm³ ofice-cold water. The precipitate formed is filtered, washed three timeswith water and dried under vacuum (2.7 kPa) to give 4.42 g of1-[4-(3-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone in the form of acream solid.

IR spectrum (KBr): 3125; 2687; 2577; 1729; 1616; 1529; 1391; 1318; 1256;1219; 945; 791; 715 and 629 cm⁻¹.

The 4-(3-bromophenyl)-1H-pyrazol-3-ol can be prepared in the followingway:

A solution, with stirring, of 12.22 g of methyl ester of2-(3-bromophenyl)-3-dimethylaminoacrylic acid and of 2.1 cm³ ofhydrazine monohydrate in 100 cm³ of ethanol is heated at the reflux ofthe solvent for 3 h. The reaction mixture is evaporated to dryness underreduced pressure (2.7 kPa) and the residue is triturated in diisopropylether. The solid formed is filtered and is dried under vacuum (2.7 kPa)to give 5.1 g of dimethylammonium 4-(3-bromophenyl)-1H-pyrazol-3-olatein the form of a cream solid. The filtrate is evaporated under reducedpressure (2.7 kPa), the residue is triturated in diisopropyl ether, andthe solid formed is filtered and dried under vacuum (2.7 kPa), resultingin 4.3 g of 4-(3-bromophenyl)-1H-pyrazol-3-ol in the form of a creamsolid.

IR spectrum (KBr): 3099; 2768; 2668; 1620; 1590; 1410; 1241; 1081; 787;712 and 689 cm⁻¹.

The methyl ester of 2-(3-bromophenyl)-3-dimethylaminoacrylic acid can beprepared in the following way:

14.4 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine are addedto a solution of 10.5 g of methyl ester of 2-(3-bromophenyl)acrylic acidin 100 cm³ of tetrahydrofuran and the mixture is heated at the reflux ofthe solvent for 2.5 h. After stirring for 15 h at a temperature in theregion of 20° C., the reaction mixture is evaporated to dryness underreduced pressure (2.7 kPa). The residue is taken up with ethyl acetate,and the organic solution is washed with 3 times water, and then driedover magnesium sulfate, filtered and evaporated under reduced pressure(2.7 kPa) to give 12.22 g of methyl ester of2-(3-bromophenyl)-3-dimethylaminoacrylic acid in the form of a yellowoil.

IR spectrum (CCl₄): 2947; 2813; 1691; 1603; 1432; 1285; 1221; 1098 and694 cm⁻¹.

EXAMPLE 33 4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-oldihydrochloride

1 cm³ of 3N hydrochloric diethyl ether is added to a solution of 121 mgof {2-[3-benzyloxy-4-biphenyl-3-ylpyrazol-1-yl]ethyl}dimethylamine in 20cm³ of ethanol. After stirring for 30 min at a temperature in the regionof 20° C., the solution is evaporated to dryness under reduced pressure(2.7 kPa). The residue is taken up with 20 cm³ of ethanol. The solutionobtained is introduced into an autoclave, 11 mg of palladium-on-charcoalat 10% are added, and it is then placed under hydrogen (7 bar). Afterstirring for 5 h at 30° C., the reaction medium is filtered oversupercel, and the filtrate is evaporated. Diisopropyl ether is added tothe residue, resulting in a suspension which is heated at the reflux ofthe solvent and filtered under hot conditions. The resulting solid isdried under vacuum (2.7 kPa) to give 69 mg of4-biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol dihydrochloridein the form of a white powder.

IR spectrum (KBr): 3054; 2959; 2685; 2299; 1606; 1522; 1457; 1298; 1182;760; 698 and 671 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.79 (unresolved peak:6H); 3.43 (unresolved peak: 2H); 4.31 (unresolved peak: 2H); from 7.25to 7.55 (mt: 5H); 7.68 (mt: 3H); 7.94 (broad s: 1H); 8.15 (s: 1H); from9.45 to 9.65 (broad unresolved peak: 1H); 10.49 (broad s: 1H).

The {2-[3-benzyloxy-4-biphenyl-3-ylpyrazol-1-yl]ethyl}-dimethylamine canbe prepared in the following way:

503 mg of phenylboronic acid, 891 mg of potassium phosphate and 217 mgof bis(triphenylphosphine)-palladium chloride are added to a stirredsolution of 550 mg of{2-[3-benzyloxy-4-(3-bromophenyl)pyrazol-1-yl]ethyl}dimethylamine in 25cm³ of toluene under an argon atmosphere. After heating at the reflux ofthe solvent for 15 h, 168 mg of phenylboronic acid, 297 mg of potassiumphosphate and 148 mg of bis(triphenylphosphine)palladium chloride areadded to the reaction medium and the reaction is continued at the sametemperature for 15 h. The mixture is then cooled to a temperature in theregion of 20° C., ethyl acetate and water are added, and it is filteredover supercel. The filtrate is separated by settling out, and theorganic phase is then washed successively with 0.5N sodium hydroxide,water and a saturated aqueous sodium chloride solution; it is dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa). The brown oil obtained (1.2 g) is purified by flash chromatographyon alumina CTB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (80/20 by volume)]. After concentration of thefractions under reduced pressure, 300 mg of an orange-colored oil areobtained, which is again used in a reaction for 15 h with 25 cm³ oftoluene, 503 mg of phenylboronic acid, 891 mg of potassium phosphate and217 mg of bis(triphenylphosphine)palladium chloride according to theprotocol described above. A brown oil is obtained (800 mg), which ispurified by flash chromatography on alumina CTB1 under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. Afterconcentration of the fractions under reduced pressure (2.7 kPa), 120 mgof {2-[3-benzyloxy-4-biphenyl-3-yl-pyrazol-1-yl]ethyl}dimethylamine areobtained in the form of a yellow oil.

IR spectrum (CCl₄): 3065; 3033; 2823; 2774; 1609; 1579; 1505; 1450; 1240and 699 cm⁻¹.

EXAMPLE 341-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-4-yl)-1H-pyrazol-3-oldihydrochloride

0.06 cm³ of 12N hydrochloric acid is added to a solution of 200 mg of{2-[3-benzyloxy-4-(4′-fluorobiphenyl-4-yl)pyrazol-1-yl]ethyl}dimethylaminein 20 cm³ of ethanol. The mixture is introduced into an autoclave, 28 mgof palladium-on-charcoal at 10% are added, and it is then placed underhydrogen (5 bar). After stirring for 4 h at 40° C., the reaction mediumis filtered over supercel and the filtrate is evaporated. The residue istriturated in diisopropyl ether. The solid obtained, dissolved in 20 cm³of ethanol, is used again in a reaction in an autoclave with 10 mg ofpalladium-on-charcoal at 10% and under hydrogen (7 bar). After stirringfor 5 h at 35° C., the reaction mixture is filtered over supercel andthe filtrate is evaporated. The residue is triturated in diisopropylether, filtered and dried under vacuum (2.7 kPa) to give 77 mg of1-(2-dimethylaminoethyl)-4-(4′-fluorobiphenyl-4-yl)-1H-pyrazol-3-oldihydrochloride in the form of a beige solid.

IR spectrum (KBr): 2964; 2676; 2468; 1611; 1585; 1528; 1514; 1493; 1460;1234; 1161; 826; 810 and 511 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.79 (broad s: 6H);3.48 (unresolved peak: 2H); 4.36 (broad t, J=6, 5 Hz: 2H); 7.30 (broadt, J=9 Hz: 2H); 7.65 (broad d, J=8 Hz: 2H); from 7.70 to 7.80 (mt: 4H);8.09 (s: 1H); 9.92 (unresolved peak: 1H); 10.52 (broad s: 1H).

The{2-[3-benzyloxy-4-(4′-fluorobiphenyl-4-yl)pyrazol-1-yl]ethyl}dimethylaminecan be prepared in the following way:

770 mg of 4-fluorophenylboronic acid, 1.19 g of potassium phosphate and290 mg of bis(triphenylphosphine)palladium chloride are added to astirred solution of 500 mg of{2-[3-benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]ethyl}dimethylamine in 25cm³ of toluene under an argon atmosphere. After heating at the reflux ofthe solvent for 15 h, the reaction mixture is cooled to a temperature inthe region of 20° C., ethyl acetate and water are added, and it isfiltered over supercel. The filtrate is separated by settling out, andthe organic phase is then washed successively with 0.5N sodiumhydroxide, water and a saturated aqueous sodium chloride solution; it isdried over magnesium sulfate, filtered and evaporated under reducedpressure (2.7 kPa). The brown oil obtained (800 mg) is purified by flashchromatography on alumina CTB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (80/20 by volume)]. After concentration of thefractions under reduced pressure (2.7 kPa), 220 mg of{2-[3-benzyloxy-4-(4′-fluorobiphenyl-4-yl)pyrazol-1-yl]ethyl}dimethylamineare obtained in the form of a yellow oil.

Mass spectrum (EI): m/z 415 (M^(+.)), m/z 344 [(M-C₄H₉N)⁺], m/z 91 (C₇H₇⁺), m/z 58 (C₃H₈N⁺).

The {2-[3-benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]-ethyl}dimethylaminecan be prepared in the following way:

A solution of 5.2 g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in 50cm³ of dimethylformamide is added to a suspension of 1.36 g of sodiumhydride (at 75% in liquid petroleum jelly) in 50 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred for 1 h at atemperature in the region of 20° C., and is then cooled in an ice bathand a solution of 5.5 g of (2-bromoethyl)dimethylamine in 50 cm³ ofdimethylformamide is added. The reaction medium is stirred for 15 h at atemperature in the region of 20° C., and is then cooled to a temperaturein the region of 20° C. and poured into 400 cm³ of water. The aqueousphase is extracted twice with ethyl acetate. The organic phases arepooled, washed successively with water twice and a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa) to give a brown oil which ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: ethyl acetate, ethyl acetate/methanol (90/10 by volume)].After concentration of the fractions under reduced pressure, 2.3 g of{2-[3-benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]ethyl}dimethylamine areobtained in the form of a yellow oil.

Mass spectrum (EI): m/z 399 (M^(+.)), m/z 328 [(M-C₄H₉N)+], m/z 91 (C₇H₇^(+.)), m/z 58 (C₃H₈N⁺).

The 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole can be prepared in thefollowing way:

3.88 g of potassium carbonate and 3.1 cm³ of benzyl bromide are added toa suspension of 6.58 g de1-[3-benzyloxy-4-(4-bromophenyl)pyrazol-1-yl]ethanone in 70 cm³ ofmethyl ethyl ketone with stirring. The mixture is heated at the refluxof the solvent for 2.5 h, cooled to a temperature in the region of 20°C., and filtered. The filtrate is evaporated under reduced pressure (2.7kPa), and the residue is taken up with 50 cm³ of tetrahydrofuran and 50cm³ of methanol and 1.5 cm³ of 10N sodium hydroxide are then added.After stirring for 30 min at a temperature in the region of 20° C., thereaction medium is evaporated under reduced pressure (2.7 kPa). Thereaction crude is taken up in dichloromethane. The organic phase iswashed successively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa). The solid obtained is triturated indiisopropyl ether, filtered and dried under vacuum (2.7 kPa) to give 2.9g of 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in the form of a beigesolid. The filtrate is evaporated under reduced pressure (2.7 kPa) andthe residue is taken up with dichloromethane. The organic solution iswashed with water and a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and evaporated under reducedpressure (2.7 kPa). The resulting solid is triturated in diisopropylether, filtered and dried under vacuum (2.7 kPa) to give a further 2.3 gof 3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole in the form of a beigesolid.

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): 5.35 (s: 2H); 7.35(broad t, J=7.5 Hz: 1H); 7.42 (broad t, J=7.5 Hz: 2H); 7.50 (broad d,J=7.5 Hz: 2H); 7.51 (broad d, J=8.5 Hz: 2H); 7.65 (broad d, J=8.5 Hz:2H); 8.09 (s: 1H).

The 1-[4-(4-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone can be preparedin the following way:

A solution of 6 g of 4-(4-bromophenyl)-1H-pyrazol-3-ol in 50 cm³ ofpyridine, under an argon atmosphere and with stirring, is heated to 90°C., and 2.25 cm³ of acetic anhydride are then added dropwise. Afterheating at 90° C. for 1 h, the reaction medium is cooled to atemperature in the region of 20° C. and poured into 150 cm³ of ice-coldwater. The precipitate formed is filtered, washed three times with waterand dried under vacuum (2.7 kPa) to give 6.6 g of1-[4-(4-bromophenyl)-3-hydroxypyrazol-1-yl]ethanone in the form of awhite solid.

IR spectrum (KBr): 3132; 2968; 2696; 2653; 1714; 1621; 1533; 1417; 1392;1328; 1279; 1231; 1008; 949; 822; 645 and 508 cm⁻¹.

The 4-(4-bromophenyl)-1H-pyrazol-3-ol can be prepared in the followingway:

A solution, with stirring, of 11.5 g of ethyl ester of2-(4-bromophenyl)-3-dimethylaminoacrylic acid and of 1.9 cm³ ofhydrazine monohydrate in 100 cm³ of ethanol is heated at the reflux ofthe solvent for 3 h. The reaction mixture is evaporated to dryness underreduced pressure (2.7 kPa) and the residue is triturated in diisopropylether. The solid formed is filtered and is dried under vacuum (2.7 kPa)to give 6 g of 4-(4-bromophenyl)-1H-pyrazol-3-ol in the form of a whitesolid.

IR spectrum (KBr): 3299; 3123; 2958; 2674; 1606; 1579; 1517; 1488; 1399;1163; 1080; 1008; 824 and 509 cm⁻¹.

The ethyl ester of 2-(4-bromophenyl)-3-dimethylaminoacrylic acid can beprepared in the following way:

13.5 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine are addedto a solution of 10 g of ethyl ester of 2-(4-bromophenyl)acrylic acid in100 cm³ of tetrahydrofuran and the mixture is heated at the reflux ofthe solvent for 3 h. After stirring for 15 h at a temperature in theregion of 20° C., the reaction mixture is evaporated to dryness underreduced pressure (2.7 kPa). The residue is taken up with ethyl acetate,and the organic solution is washed 3 times with water and then driedover magnesium sulfate, filtered and evaporated under reduced pressure(2.7 kPa) to give 11.3 g of ethyl ester of2-(4-bromophenyl)-3-dimethylaminoacrylic acid in the form of a yellowoil.

Mass spectrum (CI): m/z 298 (MH⁺).

EXAMPLE 35 1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-3-oldihydrochloride

10 cm³ of 4N hydrochloric dioxane are added to a solution of 1.6 g of2-[3-(cyclohex-2-enyloxy)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridinein 20 cm³ of dioxane. After stirring for 15 h at a temperature in theregion of 20° C., the suspension is filtered, and the solid is rinsedonce with dioxane and then three times with diisopropyl ether, and isdried under vacuum (2.7 kPa) to give 55 mg of1-(2-piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-3-ol dihydrochloridein the form of a white powder.

IR spectrum (KBr): 3037; 2943; 2644; 2541; 1633; 1606; 1577; 1454; 1179;782 and 685 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.95 (mt: 2H); from 3.35 to 3.55 (mt: 4H); 4.57(t, J=6.5 Hz: 2H); 7.58 (mt: 1H); 8.15 (broad d, J=7 Hz: 1H); 8.31(broad t, J=7 Hz: 1H); 8.61 (broad d, J=5 Hz: 1H); 8.69 (broad s: 1H);10.64 (unresolved peak: 1H).

The2-[3-(cyclohex-2-enyloxy)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridinecan be prepared in the following way:

A suspension of 1.5 g of2-[3-(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine in 20 cm³ ofdimethylformamide is added to a suspension of 500 mg of sodium hydride(at 75% in liquid petroleum jelly) in 15 cm³ of dimethylformamide underan argon atmosphere and with stirring. After heating at 50° C. for 30min, the mixture is stirred for 30 min at a temperature in the region of20° C., and a solution of 1.6 g of 1-(2-chloroethyl)-piperidinehydrochloride is then added. The reaction medium is stirred for 15 h ata temperature in the region of 20° C. and is then poured into water. Theaqueous phase is extracted twice with ethyl acetate. The organic phasesare pooled, washed successively with water and a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa) to give a yellow oil whichis purified by flash chromatography on alumina CTB1 under an argonpressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 by volume)].After concentration of the fractions under reduced pressure, 1.6 g of2-[3-(cyclohex-2-enyloxy)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridineare obtained in the form of a pale yellow oil.

Mass spectrum (EI): m/z 352 (M^(+.)), m/z 271 [(M-C₆H₉)⁺], m/z 111(C₇H₁₃N^(+.)), m/z 98 (C₆H₁₂N⁺).

The 2-[3-(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine can be preparedin the following way:

5.4 g of potassium carbonate and 4.6 cm³ of 3-bromocyclohexene are addedto a suspension of 7.1 g of1-(3-hydroxy-4-pyridin-2-ylpyrazol-1-yl)ethanone in 70 cm³ of methylethyl ketone with stirring. The mixture is heated at the reflux of thesolvent for 4 h, cooled to a temperature in the region of 20° C., andevaporated under reduced pressure (2.7 kPa). The residue is taken upwith 50 cm³ of tetrahydrofuran and 50 cm³ of methanol, and 7 cm³ of 5Nsodium hydroxide are then added along with water until completesolubilization of the medium. After stirring for 15 h at a temperaturein the region of 20° C., the reaction medium is evaporated under reducedpressure (2.7 kPa). The reaction crude is taken up with ethyl acetateand water. The insoluble solid is filtered off and dried under reducedpressure (2.7 kPa) to give 5.3 g of2-[3-(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine in the form of awhite powder.

IR spectrum (KBr): 3180; 2928; 2723; 1602; 1533; 1497; 1463; 1288; 1065;786 and 700 cm⁻¹.

The 1-(3-hydroxy-4-pyridin-2-ylpyrazol-1-yl)ethanone can be prepared inthe following way:

A solution, stirred and under an argon atmosphere, of 7.3 g of4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloride in 70 cm³ of pyridine isheated to 100° C., and 3.75 cm³ of acetic anhydride are then addeddropwise. After heating at 100° C. for 1.5 h, the reaction medium iscooled to a temperature in the region of 20° C. and is poured into 150cm³ of ice-cold water. The precipitate formed is filtered, washed threetimes with water and dried under vacuum (2.7 kPa) to give 7.1 g of1-(3-hydroxy-4-pyridin-2-ylpyrazol-1-yl)ethanone in the form of a paleyellow solid.

IR spectrum (KBr): 3157; 2396; 1719; 1608; 1391; 1274; 1223; 1000; 929;790 and 618 cm⁻¹.

The 4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloride can be prepared in thefollowing way:

A solution, with stirring, of 18 g of ethyl ester of3-dimethylamino-2-pyridin-2-ylacrylic acid and of 3.95 cm³ of hydrazinemonohydrate in 120 cm³ of ethanol is heated at the reflux of the solventfor 3 h. The reaction mixture is concentrated under reduced pressure(2.7 kPa), 3N hydrochloric ethanol is added, and the mixture is cooledin an ice bath. The solid formed is filtered, and is dried under vacuum(2.7 kPa) to give 11.3 g of 4-pyridin-2-yl-1H-pyrazol-3-ol hydrochloridein the form of a yellow solid.

IR spectrum (KBr): 3166; 1644; 1620; 1587; 1551; 1430; 1209; 1159; 907;774 and 518 cm⁻¹.

The ethyl ester of 3-dimethylamino-2-pyridin-2-ylacrylic acid can beprepared in the following way:

20 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine are added toa solution of 13 g of ethyl ester of 2-pyridin-2-ylacrylic acid in 100cm³ of tetrahydrofuran, heating is carried out at the reflux of thesolvent for 15 h, and the reaction mixture is then cooled to atemperature in the region of 20° C. and evaporated to dryness underreduced pressure (2.7 kPa). The resulting brown oil is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (90/10 by volume)]. After concentration of thefractions under reduced pressure, 18 g of ethyl ester of3-dimethylamino-2-pyridin-2-ylacrylic acid are obtained in the form ofan orange-colored oil.

IR spectrum (CCl₄): 2980; 2929; 1686; 1619; 1602; 1297; 1271; 1219; 1096and 1085 cm⁻¹.

EXAMPLE 36 1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-oldihydrochloride monohydrate

7 cm³ of 12N hydrochloric acid are added to a stirred solution of 720 mgof 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine in7 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 hat a temperature in the region of 20° C., the reaction medium isevaporated under reduced pressure (2.7 kPa). The residue is taken upwith ethanol, and the mixture is then evaporated to dryness underreduced pressure (2.7 kPa). The operation is repeated twice, ethanol isthen added to the solid and the mixture is heated at the reflux of thesolvent. After cooling of the solution in an ice bath, the crystalsformed are filtered off and dried under vacuum (2.7 kPa) to give 300 mgof 1-(2-piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-oldihydrochloride monhydrate in the form of a white solid.

IR spectrum (KBr): 3495; 3414; 3197; 2934; 2652; 2545; 1637; 1599; 1540;1513; 1206; 813 and 523 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to 1.60(very broad unresolved peak: 1H); from 1.60 to 1.90 (mt: 5H); from 2.85to 3.05 (unresolved peak: 2H); from 3.30 to 3.45 (mt: 2H); 3.49 (t,J=6.5 Hz: 2H); 4.54 (t, J=6.5 Hz: 2H); 8.12 (broad d, J=7 Hz: 2H); 8.67(s: 1H); 8.69 (broad d, J=7 Hz: 2H); 11.75 (unresolved peak: 1H).

The 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridinecan be prepared in the following way:

A solution of 720 mg of 4-(3-benzyloxy-1H-pyrazol-4-yl)pyridine in 20cm³ of dimethylformamide is added to a suspension of 230 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 10 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred for 30 min at atemperature in the region of 20° C., and a solution of 740 mg of1-(2-chloroethyl)piperidine hydrochloride is then added. The reactionmedium is stirred for 15 h at a temperature in the region of 20° C. andis then poured into water. The aqueous phase is extracted twice withethyl acetate. The organic phases are pooled, washed successively withwater and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give an orange-colored oil which is purifed by flashchromatography on alumina CTB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (90/10, then 80/20 by volume)]. Afterconcentration of the fractions under reduced pressure, 720 mg of4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine areobtained in the form of a pale yellow oil.

IR spectrum (CH₂Cl₂): 2940; 1604; 1573; 1513; 1453; 1363; 1172; 992;815; 676 and 534 cm⁻¹.

The 4-(3-benzyloxy-1H-pyrazol-4-yl)pyridine can be prepared in thefollowing way: 1.8 g of potassium carbonate and 1.55 cm³ of benzylbromide are added to a suspension of 2.4 g of1-(3-hydroxy-4-pyridin-4-ylpyrazol-1-yl)ethanone in 25 cm³ of methylethyl ketone with stirring. The mixture is heated at the reflux of thesolvent for 3 h, cooled to a temperature in the region of 20° C., andfiltered. The filtrate is evaporated under reduced pressure (2.7 kPa).The resulting brown oil is purified by flash chromatography on silicaunder an argon pressure (50 kPa) [eluent: ethyl acetate/cyclohexane(80/20 by volume)]. After concentration of the fractions under reducedpressure, 720 mg of 4-(3-benzyloxy-1H-pyrazol-4-yl)pyridine are obtainedin the form of a white solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.27 (s: 2H); 7.36(tt, J=7.5 and 1.5 Hz: 1H); 7.44 (tt, J=7.5 and 1.5 Hz: 2H); 7.52 (broadd, J=7.5 Hz: 2H); 7.66 (dd, J=5 and 2 Hz: 2H); 8.33 (s: 1H); 8.47 (dd,J=5 and 2 Hz: 2H); from 12.25 to 12.50 (unresolved peak: 1H).

The 1-(3-hydroxy-4-pyridin-4-ylpyrazol-1-yl)ethanone can be prepared inthe following way:

A suspension of 2.5 g of 4-pyridin-4-yl-1H-pyrazol-3-ol hydrochloride in25 cm³ of pyridine, with stirring and under an argon atmosphere, isheated to 100° C., and 1.25 cm³ of acetic anhydride are then addeddropwise. After heating at 100° C. for 2 h, the reaction medium iscooled in an ice bath. The solid formed is filtered off, washed withwater and then with heptane, and dried under vacuum (2.7 kPa) to give1-(3-hydroxy-4-pyridin-4-ylpyrazol-1-yl)ethanone, which is used directlyin the following step.

The 4-pyridin-4-yl-1H-pyrazol-3-ol hydrochloride can be prepared in thefollowing way:

A solution, with stirring, of 12.46 g of ethyl ester of3-dimethylamino-2-pyridin-4-ylacrylic acid and of 2.75 cm³ of hydrazinemonohydrate in 80 cm³ of ethanol is heated at the reflux of the solventfor 3 h. The reaction mixture is cooled in an ice bath, and the solidformed is filtered off and taken up with water. The suspension isadjusted to pH 6 with 1N hydrochloric acid and is then filtered. Thesolid obtained is washed with water and is dried under vacuum (2.7 kPa)to give 5.1 g of 4-pyridin-4-yl-1H-pyrazol-3-ol hydrochloride in theform of a yellow solid.

IR spectrum (KBr): 3355; 2464; 2059; 1965; 1637; 1575; 1527; 1207; 1193;1075; 1022; 914; 838 and 519 cm⁻¹.

The ethyl ester of 3-dimethylamino-2-pyridin-4-ylacrylic acid can beprepared in the following way:

24 cm³ of C-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine are added toa solution of 15 cm³ of ethyl ester of 2-pyridin-4-ylacrylic acid in 100cm³ of tetrahydrofuran and heating is carried out at the reflux of thesolvent for 15 h, and the reaction mixture is then evaporated to drynessunder reduced pressure (2.7 kPa). The residue is taken up with ethylacetate, and the organic solution is washed twice with water and asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa). Thebrown oil obtained is purified by flash chromatography on silica underan argon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 byvolume)]. After concentration of the fractions under reduced pressure,12.46 g of ethyl ester of 2-pyridin-4-ylacrylic acid are obtained in theform of an orange-colored oil.

IR spectrum (CCl₄): 2981; 1690; 1596; 1280; 1218; 1095 and 1051 cm⁻¹.

EXAMPLE 37 4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol

0.5 g of3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolehydrochloride is introduced into an autoclave with 12.8 mg ofpalladium-on-charcoal (at 10%) and 25 cm³ of ethanol. The device isplaced under a hydrogen pressure of 500 kPa at a temperature of 25° C.for 5 hours. After cooling to a temperature in the region of 20° C., thereaction medium is filtered over supercel; the filtrate is washed with 3times 100 cm³ of ethanol, and concentrated to dryness under reducedpressure (2 kPa). The residue obtained is purified by chromatography,under a nitrogen pressure of 50 kPa, on a column of silica gel (particlesize 20-45μ; diameter 1 cm; height 25 cm), eluting with a mixture ofdichloromethane and of a 2N solution of ammoniacal methanol (93/7 byvolume). Concentration is performed under reduced pressure (2 kPa); 160mg of 4-(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol areobtained in the form of a white solid.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to 1.55 (mt:6H); 2.40 (broad t, J=5.5 Hz: 4H); 2.65 (t, J=7 Hz: 2H); 4.00 (t, J=7Hz: 2H); 7.15 (t, J=9 Hz: 2H); 7.65 (dd, J=9 and 5.5 Hz: 2H); 7.91 (s:1H); 10.32 (broad s: 1H). Mass spectrum (EI): m/z 289 (M^(+.)), m/z 98(base peak).

The 3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolecan be prepared in the following way:

A suspension of 0.80 g of3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 1.12 g of4-fluorophenylboronic acid, 0.20 g ofdichlorobis(triphenylphosphine)palladium and 1.88 g of potassiumphosphate in 30 cm³ of 1,2-dimethoxyethane is stirred, under an argonatmosphere, at the boiling temperature of the reaction medium, for 14hours. After cooling, 30 cm³ of a saturated sodium hydrogen carbonatesolution are added to the mixture, which is extracted with 30 cm³ ofethyl acetate. The organic phase is dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (3 kPa). Theresidue is purified by chromatography on silica gel, eluting with amixture of ethyl acetate and methanol (30/1 by volume). Afterconcentration of the fractions under reduced pressure, 0.57 g of ayellowish oil is obtained, which is used as it is in the following step.0.57 g of3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole istaken up with 5 cm³ of diethyl ether and 0.5 cm³ of a 4N solution ofhydrochloric acid in diethyl ether. The precipitate formed is filteredover dried. 0.5 g of3-benzyloxy-4-(4-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole isobtained. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to1.50 (mt: 1H); from 1.60 to 1.85 (mt: 5H); 2.91 (mt: 2H); 3.44 (verybroad d, J=12.5 Hz: 2H); 3.52 (mt: 2H); 4.47 (broad t, J=6.5 Hz: 2H);5.34 (s: 2H); 7.72 (t, J=9 Hz: 2H); from 7.30 to 7.45 (mt: 3H); 7.51(broad d, J=7.5 Hz: 2H); 7.68 (dd, J=9 and 6 Hz: 2H); 8.16 (s: 1H); from9.70 to 10.00 (unresolved peak: 1H).

The 3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-pyrazole can beprepared in the following way:

5.6 g of sodium hydride (at 75% by mass in liquid petroleum jelly) and25 cm³ of anhydrous dimethylformamide are added gradually, at atemperature in the region of 5° C., to a solution of 8 g of3-benzyloxy-4-bromo-1H-pyrazole hydrochloride in 100 cm³ of anhydrousdimethylformamide. After stirring for 1 hour at ambient temperature,6.93 g of 1-(2-chloroethyl)piperidine hydrochloride and 30 cm³ ofanhydrous dimethylformamide are added in small portions. After stirringfor 21 hours at ambient temperature, the excess sodium hydride isdestroyed by slowly adding water, and the reaction medium is then runinto 1 dm³ of water and extracted with 2 times 200 cm³ of ethyl acetate.The pooled organic phases are dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is taken up with 20 cm³ of acetone and run into a solution of3.6 g of oxalic acid in 30 cm³ of acetone. The solid formed istriturated and then isolated by filtration and dried at ambienttemperature, to give 11.3 g of3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate. 50cm³ of a saturated sodium hydrogen carbonate solution are added to 5 gof this oxalate and the mixture is extracted with 2×100 cm³ of ethylacetate. The pooled organic phases are dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (3 kPa).3.84 g of 3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-pyrazole arethus obtained in the form of a light oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.55 (mt:6H); 2.35 (broad t, J=5 Hz: 4H); 2.61 (t, J=6.5 Hz: 2H); 4.04 (t, J=6.5Hz: 2H); 5.20 (s: 2H); from 7.30 to 7.50 (mt: 5H); 7.81 (s: 1H).

The 3-benzyloxy-4-bromo-1H-pyrazole hydrochloride can be prepared in thefollowing way:

A solution of 2.6 cm³ of bromine in 50 cm³ of dichloromethane is addeddropwise, over 0.5 hour, to a suspension of 8.76 g of3-benzyloxy-1H-pyrazole and 11 g of sodium carbonate in 100 cm³ ofdichloromethane, which has been cooled and kept at around 5° C. withstirring. After stirring for 0.5 hour at this temperature, 20 cm³ of0.1N sodium thiosulfate solution is added to the mixture, which isstirred for a further 1 hour at around 5° C., and then 100 cm³ ofdichloromethane are added and the mixture is separated by settling out.The organic phase is extracted again with 50 cm³ of water and theorganic phases are pooled and dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (3 kPa). The oily residueobtained is taken up with 10 cm³ of 6N hydrochloric dioxane and thesolid formed is triturated in ethyl ether and isolated by filtration.12.5 g of 3-benzyloxy-4-bromo-1H-pyrazole are thus obtained in the formof a white solid which melts at around 80° C. (with decomposition).

Mass spectrum (EI): m/z 252 (M^(+.)), m/z 91 (base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.22 (s: 2H); from7.30 to 7.50 (mt: 5H); 7.81 (s: 1H); from 11.80 to 12.70 (very broadunresolved peak: 1H).

The 3-benzyloxy-1H-pyrazole can be prepared in the following way:

50 cm³ of a saturated sodium hydrogen carbonate solution are added to10.6 g of 3-benzyloxy-1H-pyrazole hydrochloride and the mixture isextracted with 2×150 cm³ of dichloromethane. The pooled organic phasesare dried over magnesium sulfate, filtered and concentrated to drynessunder reduced pressure (3 kPa) to give 8.76 g of 3-benzyloxy-1H-pyrazolein the form of an oil, which is used as it is in the following step.

The 3-benzyloxy-1H-pyrazole hydrochloride can be prepared in thefollowing way:

A suspension of 11 g of 1-(3-hydroxypyrazol-1-yl)-ethanone, 12.5 g ofpotassium carbonate and 11.3 cm³ (16.25 g) of benzyl bromide in 250 cm³of 2-butanone is stirred at the boiling temperature of the mixture for1.25 hours. The insoluble inorganic material is then removed byfiltration and the filtrate is concentrated to dryness under reducedpressure (3 kPa). The oily residue obtained is dissolved in a mixture of150 cm³ of tetrahydrofuran and 100 cm³ of methanol, and 4 cm³ of a 10Msodium hydroxide solution are then added thereto. After stirring for0.65 hour at ambient temperature, the mixture is concentrated to drynessunder reduced pressure (3 kPa). The pasty residue obtained is taken upwith 250 cm³ of ethyl acetate and washed with 2 times 10 cm³ of brine.The organic phase is dried over magnesium sulfate, filtered andconcentrated under reduced pressure (3 kPa). 100 cm³ of 1N hydrochloricether are added to the residue and the solid formed is triturated andthen isolated by filtration. The solid is solubilized in 250 cm³ ofisopropanol at around 60° C., and the mixture is then partiallyconcentrated until the first crystals appear, 5 cm³ isopropyl acetateare added, and the mixture is cooled to around 0° C. After filtrationand drying, 10.6 g of 3-benzyloxy-1H-pyrazole hydrochloride are obtainedin the form of salmon-pink crystals which melt at 100° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.16 (s: 2H); 5.75 (d,J=3 Hz: 1H); from 7.30 to 7.50 (mt: 5H); 7.57 (d, J=3 Hz: 1H).

The 1-(3-hydroxypyrazol-1-yl)ethanone can be prepared in the followingway:

A solution of 9.5 cm³ of acetic anhydride in 18 cm³ of pyridine is addedslowly, over 0.33 hours, to a solution of 8.4 g of 1H-pyrazol-3-ol (No.CAS 60456-92-0) in 38 cm³ of pyridine preheated to 95° C., and thistemperature is then maintained for 1 hour. The mixture is thenconcentrated under reduced pressure (3 kPa). 100 cm³ of ethyl ether areadded to the residual suspension, which is triturated to finish off thecrystallization. After filtration and drying, 11 g of1-(3-hydroxypyrazol-1-yl)ethanone are obtained in the form of whitishcrystals which sublimate at around 215° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.50 (s: 3H); 6.02 (d,J=3 Hz: 1H); 8.15 (d, J=3 Hz: 1H); from 10.80 to 11.20 (unresolved peak:1H).

EXAMPLE 384-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

600 mg of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolein 4.5 cm³ of ethanol and 4.5 cm³ of 12N hydrochloric acid are broughtto reflux at a temperature in the region of 100° C. for 7 hours. Aftercooling to a temperature in the region of 20° C., the reaction medium isconcentrated to dryness under reduced pressure (2 kPa); the residue isprecipitated from a mixture of diisopropyl ether and acetone. 464 mg of4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride are obtained in the form of a white powder.

IR spectrum (KBr): 3428; 2951; 2642; 2538; 1615; 1591; 1533; 1456; 1275;1219; 1159; 1012; 856 and 806 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.41 (mt: 1H); from1.60 to 1.85 (mt: 5H); 2.94 (unresolved peak: 2H); 3.46 (mt: 4H); 4.41(mt: 2H); 7.34 (broad d, J=8 Hz: 2H); 7.76 (d, J=8 Hz: 2H); 8.09 (s:1H); 10.04 (broad unresolved peak: 1H); 10.62 (broad s: 1H).

The3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolecan be prepared in the following way:

560 mg of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole in 15 cm³of anhydrous dimethylformamide are cooled, with stirring, to atemperature in the region of −5° C. and under an inert atmosphere; 140mg of sodium hydride (at 75% in liquid petroleum jelly) are addedportionwise to the reaction medium and the temperature is allowed toreturn to approximately 20° C. 431 mg of 1-(2-chloroethyl)piperidinehydrochloride are then added and the stirring is maintained at thistemperature for 15 hours. The reaction medium is taken up with 300 cm³of ice-cold water and 300 cm³ of ethyl acetate. The organic phase isseparated by settling out, washed with 200 cm³ of water and concentratedto dryness under reduced pressure (2 kPa). The residue is purified on anFC50SI-HP silica cartridge, eluting with a mixture of dichloromethaneand methanol (95/5 by volume). The product obtained is again purified onan FC50SI-HP silica cartridge, eluting with a mixture of dichloromethaneand methanol (98/2 by volume). 600 mg of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleare obtained in the form of a colorless oil. Mass spectrum (CI): m/z 446([M+H]⁺) (base peak).

The 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole can be preparedin the following way:

1.07 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,5 cm³ of a 1N solution of n-tetrabutylammonium fluoride intetrahydrofuran and 50 cm³ of tetrahydrofuran are heated, with stirring,at the reflux of the solvent for 15 hours. The reaction medium is cooledto a temperature in the region of 20° C., and taken up with 300 cm³ ofethyl acetate and 100 cm³ of water. The organic phase is separated bysettling out, dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2 kPa). The residueobtained is purified on an FC50SI-HP silica cartridge, eluting withdichloromethane. 560 mg of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole are obtained in theform of a powder. Mass spectrum (EI): m/z 334 (M^(+.)), m/z 91 (basepeak).

The3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-pyrazolecan be prepared in the following way:

2.04 g of 4-trifluoromethoxyphenylboronic acid, 4.96 cm³ of a 2N aqueouspotassium carbonate solution and 496 mg oftetrakis(triphenylphosphine)palladium are added to a solution of 1.5 gof 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in a mixture of40 cm³ of toluene and ethanol (4/1 by volume) in a three-necked flask.The three-necked flask containing the reaction medium is placed in abath preheated to a temperature in the region of 120° C.; the stirringis continued for 90 minutes at this temperature. The mixture is thencooled to a temperature in the region of 20° C., and filtered oversupercel. The filtrate is taken up with 300 cm³ of ethyl acetate and 100cm³ of water. The organic phase is separated by settling out andconcentrated to dryness under reduced pressure (2 kPa). The residueobtained is purified on an FC50SI-HP silica cartridge, eluting with amixture of cyclohexane and ethyl acetate (90/10 by volume). 1.07 g of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-pyrazoleare obtained in the form of a yellow powder. Mass spectrum (CI): m/z 489([M+H]⁺), m/z 335 (base peak).

The 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole can beprepared in the following way:

5 g of 3-benzyloxy-4-(4-iodophenyl)-1H-pyrazole in 110 cm³ ofdimethylformamide are cooled while stirring, under an inert atmosphere,to a temperature in the region of −5° C. 587 mg of sodium hydride (at75% in liquid petroleum jelly) are added portionwise and the mixture isallowed to return to a temperature in the region of 20° C. 4.4 g ofpara-tolunesulfonyl chloride are then added and the stirring ismaintained at this temperature for 15 hours. The reaction medium istaken up with 300 cm³ of ice-cold water and 500 cm³ of ethyl acetate.The organic phase is separated by settling out, washed with 300 cm³ ofwater and 300 cm³ of a saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate, filtered and concentrated to drynessunder reduced pressure (2 kPa). The residue is crystallized fromdiisopropyl ether. 7.24 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained inthe form of a powder. Mass spectrum (EI): m/z 454 (M^(+.)), m/z 299, m/z91 (base peak).

The 3-benzyloxy-4-iodo-1H-pyrazole can be prepared in the following way:

A suspension of 0.32 g of 3-benzyloxy-1H-pyrazole, 0.3 g of sodiumacetate and 0.65 g of iodine in 50 cm³ of chloroform is stirred atambient temperature for 26 hours. 50 cm³ of a 0.5N sodium thiosulfatesolution are then added to the mixture, which is stirred untildecoloration is observed and separated by settling out. The aqueousphase is extracted again with 25 cm³ of chloroform. The pooled organicphases are dried over magnesium sulfate, filtered and concentrated underreduced pressure (3 kPa). The residue obtained is purified bychromatography on silica gel, eluting with a mixture of cyclohexane andethyl acetate (80/20 by volume). After concentration of the fractionsunder reduced pressure, a colorless oil is obtained which crystallizesrapidly and provides 0.4 g of 3-benzyloxy-4-iodo-1H-pyrazole in the formof a white solid having an Rf of 0.6 [mixture of cyclohexane and ethylacetate (50/50 by volume), plate of silica gel 60 F254 reference 105719,Merck]. Mass spectrum (EI): m/z 300 (M+.) (base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 5.22 (s: 2H); from7.30 to 7.50 (mt: 5H); 7.74 (s: 1H); from 12.20 to 12.60 (broadunresolved peak: 1H).

EXAMPLE 39 4-Phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-oldihydrochloride

2 cm³ of a 4N solution of hydrochloric acid in dioxane are added, at atemperature in the region of 20° C., to a mixture of 150 mg of1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidinein 5 cm³ of anhydrous methanol. The reaction medium is stirred at thistemperature for 20 hours, concentrated to dryness under reduced pressure(2 kPa), and taken up with 20 cm³ of dichloromethane. The solution isconcentrated to dryness under reduced pressure (2 kPa). The residue isprecipitated with 20 cm³ of diisopropyl ether. 110 mg of4-phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol dihydrochloride areobtained in the form of a yellow solid.

IR spectrum (KBr): 3431; 2949; 2651; 2521; 1606; 1580; 1527; 1451; 1175;1121; 1012; 765; 698 and 672 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.24 (d, J=6.5 Hz:3H); 1.44 (mt: 1H); from 1.65 to 1.95 (mt: 5H); 2.95 (mt: 1H); 3.10 (mt:1H); from 3.35 to 3.55 (mt: 2H); 3.71 (mt: 1H); 4.21 (dd, J=14.5 and 7.5Hz: 1H); 4.43 (dd, J=14.5 and 5.5 Hz: 1H); 7.15 (broad t, J=7.5 Hz: 1H);7.34 (broad t, J=7.5 Hz: 2H); 7.66 (broad d, J=7.5 Hz: 2H); 8.01 (s:1H); 9.51 (unresolved peak: 1H); 10.51 (s: 1H).

The1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidinecan be prepared in the following way:

A mixture of 0.5 g of methanesulfonic acid2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl ester, 0.4cm³ of piperidine and 1.0 g of potassium carbonate in 20 cm³ ofdimethylformamide is heated while stirring at a temperature in theregion of 80° C. for 6 hours and then for 15 hours at a temperature inthe region of 20° C. The reaction medium is taken up with 100 cm³ ofwater and 100 cm³ of ethyl acetate. The organic phase is separated bysettling out, washed with 2 times 100 cm³ of water and 100 cm³ of asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2 kPa). The residue is purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45μ; diameter 2 cm; height 40 cm), eluting with a mixture ofcyclohexane and ethyl acetate (80/20 by volume). After concentration ofthe fractions under reduced pressure (2 kPa), 150 mg of1-{2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl}piperidineare obtained in the form of a yellow oil. Mass spectrum (EI): m/z 365(M^(+.)), m/z 112 (base peak).

The methanesulfonic acid2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl ester canbe prepared in the following way:

1 cm³ of methanesulfonyl chloride and 2.59 cm³ of triethylamine areadded to a stirred solution of 550 mg of1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-propan-2-ol in 30 cm³ ofdichloromethane, at a temperature in the region of 20° C. The reactionmedium is stirred for 7 hours at a temperature in the region of 20° C.,and taken up with 50 cm³ of distilled water and 50 cm³ of ethyl acetate.The organic phase is separated by settling out, dried over anhydrousmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2 kPa). The residue is purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45μ; diameter 4 cm; height 60 cm), eluting with a mixture ofcyclohexane and ethyl acetate (80/20 by volume). After concentration ofthe fractions under reduced pressure (2 kPa), 300 mg of methanesulfonicacid 2-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-1-methylethyl esterare obtained in the form of a colorless oil. Mass spectrum (EI): m/z 376(M^(+.)), m/z 296 (base peak).

The 1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]-propan-2-ol can beprepared in the following way:

2.4 g of 3-(cyclohex-2-enyloxy)-4-phenyl-1H-pyrazole are dissolved in 25cm³ of anhydrous dimethylformamide under an inert atmosphere and withstirring. 2.24 g of potassium tert-butoxide, followed by 0.7 cm³ ofmethyloxirane are added at a temperature in the region of 20° C. Thereaction medium is heated at a temperature in the region of 60° C. for 1hour. A further 0.7 cm³ of methyloxirane is then added and the mixtureis heated for 1 hour at a temperature in the region of 60° C. Themixture is cooled to a temperature in the region of 20° C., and taken upwith 200 cm³ of water and 200 cm³ of ethyl acetate. The organic phase isseparated by settling out, washed with 3 times 200 cm³ of water and 200cm³ of a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2 kPa). The residue is purified by chromatography,under a nitrogen pressure of 50 kPa, on a column of silica gel (particlesize 20-45μ; diameter 4 cm; height 50 cm), eluting with a mixture ofcyclohexane and ethyl acetate (80/20 by volume). After concentration ofthe fractions under reduced pressure (2 kPa), 450 mg of1-[3-(cyclohex-2-enyloxy)-4-phenylpyrazol-1-yl]propan-2-ol are obtainedin the form of a colorless oil. Mass spectrum (EI): m/z 298 (M^(+.)),m/z 218, m/z 173 (base peak)

EXAMPLE 40 3-(4-Phenylpyrazol-1-ylmethyl)-1-aza-bicyclo[2.2.2]-octanedihydrochloride

A solution of 0.4 g of 3-(pyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanein 5 cm³ of dimethylformamide is added to a mixture of 0.4 g of sodiumhydride (at 75% in liquid petroleum jelly) and of 10 cm³ ofdimethylformamide. The reaction medium is heated at a temperature in theregion of 50° C. for approximately 1 hour, and the solution is thencooled to a temperature in the region of 20° C. 1.75 g of3-chloro-methylquinuclidine are added slowly, and the reaction medium isheated at a temperature in the region of 50° C. for 16 hours and thencooled to a temperature in the region of 20° C. The mixture is taken upwith 100 cm³ of water and 100 cm³ of ethyl acetate. The organic phase isseparated by settling out, washed with 2 times 100 cm³ of water and 100cm³ of a saturated aqueous sodium chloride solution, and thenconcentrated to dryness under reduced pressure (2 kPa). The residue ispurified by chromatography, under a nitrogen pressure of 50 kPa, on acolumn of alumina CTB1 (diameter 3 cm; height 40 cm), eluting with ethylacetate and then with a mixture of ethyl acetate and methanol (98/2,95/5 then 90/10 by volume), collecting fractions of 60 cm³. Fractions 14to 20 are concentrated under reduced pressure. The residue obtained ispurified a second time by chromatography, under a nitrogen pressure (50kPa), on a column of alumina CTB1 (diameter 3 cm; height 40 cm), elutingwith ethyl acetate and then with a mixture of ethyl acetate and methanol(98/2, 95/5 then 90/10 by volume), collecting fractions of 60 cm³.Fractions 14 to 20 are concentrated under reduced pressure. 150 mg of3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane are obtained.The dihydrochloride is prepared with 1.2 cm³ of a 4.7N solution ofhydrochloric acid in isopropyl ether and 5 cm³ of ethanol. 230 mg of3-(4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane dihydrochlorideare obtained.

¹H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): from 1.65 to 1.95 (mt:4H); from 2.00 to 2.15 (mt: 1H); 2.62 (mt: 1H); 2.97 (broad dd, J=13 and7 Hz: 1H); from 3.10 to 3.40 (mt: 5H); 4.25 (dd, J=13 and 8 Hz: 1H);4.32 (dd, J=13 and 8 Hz: 1H); 7.21 (broad t, J=7.5 Hz: 1H); 7.38 (t,J=7.5 Hz: 2H); 7.59 (broad d, J=7.5 Hz: 2H); 7.94 (s: 1H); 8.25 (s: 1H);10.44 (unresolved peak: 1H). Mass spectrum (EI): m/z 267 (M^(+.)) (basepeak), m/z 183, m/z 123.

The 4-phenyl-1H-pyrazole can be prepared in the following way:

1.044 g of 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole, 7 cm³ of a 1Nsolution of n-tetrabutylammonium fluoride in tetrahydrofuran and 35 cm³of tetrahydrofuran are heated at a temperature in the region of 70° C.for 6 hours. A further 3.5 cm³ of a 1N solution of n-tetrabutylammoniumfluoride in tetrahydrofuran are added and heating is continued for 15hours at this temperature. The reaction medium is cooled to atemperature in the region of 20° C., concentrated to dryness underreduced pressure (2 kPa) and then taken up with 100 cm³ of ethyl acetateand 100 cm³ of water. The organic phase is separated by settling out,washed with 100 cm³ of water and 100 cm³ of a saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2 kPa) The residueobtained is taken up with 20 cm³ of dichloromethane. The precipitate isfiltered off and dried. 0.4 g of 4-phenyl-1H-pyrazole is obtained in theform of a white powder.

Mass spectrum (EI): m/z 144 (M^(+.)) (base peak).

The 4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole can be prepared in thefollowing way:

11.72 g of phenylboronic acid are added to a stirred solution of 8.7 gof 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 200 cm³ of1,2-dimethoxyethane under an inert atmosphere. The reaction medium isheated to 110° C. and then 20.63 g of finely ground tribasic potassiumphosphate and 2.18 g of bis(triphenylphosphine)palladium chloride areadded; the mixture is heated at the reflux of the solvent for 3 hoursand then cooled to a temperature in the region of 20° C. and thenfiltered over supercel. The filtrate is taken up with 250 cm³ of ethylacetate and washed with 8 times 100 cm³ of water and 100 cm³ of asaturated aqueous sodium chloride solution. The organic phase isseparated by settling out, dried over anhydrous magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2 kPa). Theresidue is purified by chromatography, under a nitrogen pressure of 50kPa, on a column of silica gel (particle size 20-45μ; diameter 6 cm;height 45 cm), eluting with a mixture of cyclohexane and ethyl acetate(70/30 by volume), collecting fractions of 20 cm³. Fractions 6 to 12 areconcentrated under reduced pressure. 4.04 g of4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained in the form ofwhite crystals. Mass spectrum (EI): m/z 298 (M^(+.)) (base peak), m/z234, m/z 91.

The 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole can be prepared in thefollowing way:

A stirred solution of 10 g of 4-iodo-1H-pyrazole in 300 cm³ ofdimethylformamide, under an inert atmosphere, is cooled to a temperaturein the region of −3° C. 1.8 g of sodium hydride (at 75% in liquidpetroleum jelly) are added over 5 minutes and the temperature is allowedto return to approximately 20° C. 13.9 g of para-toluenesulfonylchloride are then added and the stirring is maintained for 3 hours atthis temperature. The reaction medium is taken up with 100 g of ice andthen 700 cm³ of water and 700 cm³ of ethyl acetate. The organic phase isseparated by settling out, washed with 9 times 300 cm³ of water and 2times 100 cm³ of an aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, filtered and then concentrated underreduced pressure (2 kPa). The residue is recrystallized from 1 000 cm³of diisopropyl ether. 10.9 g of4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained in the form ofwhite crystals. Mass spectrum (EI): m/z 348 (M^(+.)), m/z 284, m/z 91(base peak).

EXAMPLE 414-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The product is prepared according to the procedure described for thepreparation of4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol,using 400 mg of3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,3.3 cm³ of 12N hydrochloric acid and 3.3 cm³ of ethanol. The medium istaken up with diisopropyl ether and filtered over sintered glass. Thefiltrate is precipitated from ethanol. 160 mg of the expected productare obtained in the form of a powder.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50 (mt:1H); from 1.60 to 1.90 (mt: 5H); from 2.80 to 3.00 (unresolved peak:2H); from 3.35 to 3.50 (mt: 4H); 4.40 (broad t, J=6.5 Hz: 2H); 7.00 (d,J=5.5 Hz: 1H); 7.03 (d, J=5.5 Hz: 1H); 7.97 (s: 1H); from 10.00 to 10.30(unresolved peak: 1H); 10.78 (broad s: 1H). Mass spectrum (CI): m/z 312([M+H]⁺) (base peak).

The3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolecan be prepared in the following way:

The product is prepared according to the procedure described for thepreparation of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,using 345 mg of 3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole, 100mg of sodium hydride at 75% in liquid petroleum jelly, 305 mg of1-(2-chloroethyl)piperidine and 10 cm³ of anhydrous dimethylformamide.After purification on an FC50SI-HP silica cartridge, eluting with amixture of dichloromethane and methanol (95/5 by volume), 400 mg of theexpected product are obtained in the form of an orange-colored oil. Massspectrum (CI): m/z 402 ([M+H]⁺) (base peak).

The 3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole can be prepared inthe following way:

The product is prepared according to the procedure described for thepreparation of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,using 740 mg of3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole,3.8 cm³ of a 1N solution of n-tetrabutylammonium fluoride intetrahydrofuran and 38 cm³ of tetrahydrofuran. After purification on anFC50SI-HP silica cartridge, eluting with a mixture of dichloromethaneand methanol (95/5 by volume), 345 mg of the expected product areobtained in the form of an ecru-colored powder. Mass spectrum (EI): m/z290 (M^(+.)), m/z 91 (base peak)

The3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

589 mg of 2-bromo-5-chlorothiophene, 32.5 mg of tris(trifuryl)phosphineand 34.7 mg of tris(dibenzylideneacetone)dipalladium are added, withstirring and under an inert atmosphere, to a solution of 1.8 g of3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole in 20cm³ of dioxane. The reaction medium is heated at a temperature in theregion of 100° C. for 15 hours. The mixture is then cooled to atemperature in the region of 20° C., and filtered over supercel. Thefiltrate is concentrated to dryness under reduced pressure (2 kPa), andtaken up with cyclohexane; the insoluble material is filtered off oversintered glass, and the filtrate is concentrated to dryness underreduced pressure (2 kPa); the residue obtained is purified on anFC50SI-HP silica cartridge, eluting with a mixture of cyclohexane andethyl acetate (90/10 by volume). 200 mg of3-benzyloxy-4-(5-chlorothiophen-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrazoleare obtained in the form of a yellow powder. Mass spectrum (EI): m/z 444(M^(+.)), m/z 289 and m/z 91 (base peak).

The 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazolecan be prepared in the following way:

325 mg of triphenylphosphine, 5.9 cm³ of 1,1,1,2,2,2-hexabutyldistannaneand 141.3 mg of palladium diacetate are added, with stirring and underan inert atmosphere, to a solution of 4.4 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 45 cm³ ofdimethylformamide. The reaction medium is heated at a temperature in theregion of 80° C. for 1 hour. The mixture is then cooled to a temperaturein the region of 20° C., and filtered over supercel. The filtrate istaken up with 200 cm³ of water and 100 cm³ of ethyl acetate. The organicphase is separated by settling out, washed with 3 times 100 cm³ ofwater, dried over anhydrous magnesium sulfate, filtered and concentratedto dryness under reduced pressure (2 kPa). The residue is purified bychromatography, under a nitrogen pressure of 50 kPa, on a column ofsilica gel (particle size 20-45μ; diameter 2 cm; height 40 cm), elutingwith a mixture of cyclohexane and ethyl acetate (95/5 by volume). 4.5 gof 3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazoleare obtained in the form of a yellow oil. Mass spectrum (EI): m/z 618(M^(+.)), m/z 561 (base peak).

EXAMPLE 42 4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The product is prepared according to the procedure described for thepreparation of4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol,using 760 mg of3-benzyloxy-4-(3-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,6.5 cm³ of 12N hydrochloric acid and 6.5 cm³ of ethanol. The medium isconcentrated to dryness under reduced pressure (2 kPa); the residue isprecipitated from ethanol. 232 mg of the expected product are obtainedin the form of a powder.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50(unresolved peak: 1H); from 1.60 to 1.90 (mt: 5H); from 2.80 to 3.05(unresolved peak: 2H); from 3.35 to 3.55 (unresolved peak: 4H); 3.78 (s:3H); 4.38 (mt: 2H); 6.72 (ddd, J=7-6 and 3 Hz: 1H); from 7.15 to 7.30(mt: 3H); 8.05 (s: 1H); from 9.80 to 10.10 (broad unresolved peak: 1H);10.45 (unresolved peak: 1H). Mass spectrum (EI): m/z 301 (M^(+.)), m/z98 (base peak).

The3-benzyloxy-4-(3-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolecan be prepared in the following way:

The product is prepared according to the procedure described for thepreparation of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,using 590 mg of 3-benzyloxy-4-(3-methoxyphenyl)-1H-pyrazole, 176 mg ofsodium hydride (at 75% in liquid petroleum jelly), 542 mg of1-(2-chloroethyl)piperidine and 10 cm³ of anhydrous dimethylformamide.After purification on an FC50SI-HP silica cartridge, eluting with amixture of dichloromethane and methanol (98/2 by volume), 760 mg of theexpected product are obtained in the form of a colorless oil. Massspectrum (EI): m/z 391 (M^(+.)), m/z 98 (base peak).

The 3-benzyloxy-4-(3-methoxyphenyl)-1H-pyrazole can be prepared in thefollowing way:

The product is prepared according to the procedure described for thepreparation of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,using 1.32 g of3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole, 6.94cm³ of a 1N solution of n-tetrabutylammonium fluoride in tetrahydrofuranand 80 cm³ of tetrahydrofuran. After purification by precipitation fromdiethyl ether and purification on an FC50SI-HP silica cartridge, elutingwith a mixture of dichloromethane and methanol (95/5 by volume), 590 mgof the expected product are obtained. Mass spectrum (EI): m/z 280(M^(+.)), m/z 91 (base peak).

The 3-benzyloxy-4-(3-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

The product is prepared according to the procedure described for thepreparation of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,using 1.5 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole,1.5 g of 3-methoxyphenylboronic acid, 496 mg oftetrakis(triphenylphosphine)-palladium, and 496 cm³ of a 2N aqueoussolution of potassium carbonate in a mixture of 30 cm³ of toluene andethanol (4/1 by volume). After purification on an FC50SI-HP silicacartridge, eluting with a mixture of cyclohexane and ethyl acetate(90/10 by volume), 1.13 g of the expected product are obtained in theform of pale yellow crystals. Mass spectrum (EI): m/z 434 (M^(+.)), m/z279 and m/z 91 (base peak).

EXAMPLE 43 4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The product is prepared according to the procedure described for thepreparation of4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol,using 450 mg of3-benzyloxy-4-(2-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,3.8 cm³ of 12N hydrochloric acid and 3.8 cm³ of ethanol. The medium isconcentrated to dryness under reduced pressure (2 kPa); the residue isprecipitated from acetonitrile. 380 mg of the expected product areobtained in the form of a yellow powder.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50 (mt:1H); from 1.60 to 1.90 (mt: 5H); 2.94 (mt: 2H); from 3.30 to 3.60 (mt:4H); 3.86 (s: 3H); 4.44 (t, J=6.5 Hz: 2H); 6.95 (double doublet oftriplet, J=7.5 and 1 Hz: 1H); 7.05 (broad d, J=7.5 Hz: 1H); 7.17 (doubledoublet of triplet, J=7.5 and 1.5 Hz: 1H); 7.91 (dd, J=7.5 and 1.5 Hz:1H); 8.03 (s: 1H); from 10.10 to 10.30 (unresolved peak: 1H); from 10.20to 10.45 (broad unresolved peak: 1H).

Mass spectrum (CI): m/z 302 ([M+H]⁺) (base peak).

The3-benzyloxy-4-(2-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolecan be prepared in the following way:

The product is prepared according to the procedure described for thepreparation of3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,using 382 mg of 3-benzyloxy-4-(2-methoxyphenyl)-1H-pyrazole, 114 mg ofsodium hydride at 75% in liquid petroleum jelly, 351 mg of1-(2-chloroethyl)-piperidine and 11 cm³ of anhydrous dimethylformamide.After purification on an FC50SI-HP silica cartridge, eluting with amixture of dichloromethane and methanol (95/5 by volume), 450 mg of theexpected product are obtained in the form of a pale yellow oil. Massspectrum (EI): m/z 391 (M⁺.), m/z 98 (base peak).

The 3-benzyloxy-4-(2-methoxyphenyl)-1H-pyrazole can be prepared in thefollowing way:

The product is prepared according to the procedure described for thepreparation of 3-benzyloxy-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,using 720 mg of3-benzyloxy-4-(2-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole, 3.5cm³ of an N solution of n-tetrabutylammonium fluoride in tetrahydrofuranand 50 cm³ of tetrahydrofuran. After purification on an FC50SI-HP silicacartridge, eluting with a mixture of dichloromethane and methanol (95/5by volume), 382 mg of the expected product are obtained in the form of apinkish beige solid. Mass spectrum (EI): m/z 280 (M+.), m/z 91 (basepeak).

The 3-benzyloxy-4-(2-methoxyphenyl)-1-(tolune-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

The product is prepared according to the procedure described for thepreparation of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-trifluoromethoxyphenyl)-1H-pyrazole,using 1 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole, 1 gof 2-methoxyphenylboronic acid, 330 mg oftetrakis(triphenylphosphine)palladium, and 3.3 cm³ of a 2N aqueoussolution of potassium carbonate in a mixture of 15 cm³ of toluene andethanol (4/1 by volume). After purification on an FC50SI-HP silicacartridge, eluting with a mixture of cyclohexane and ethyl acetate(80/20 by volume), 720 mg of the expected product are obtained in theform of a beige powder. Mass spectrum (CI): m/z 435 ([M+H]+) and m/z 281(base peak).

EXAMPLE 44 4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

A stirred solution of 516 mg of4-(3-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride in 13 cm³ of dichloromethane, under an inert atmosphere,is cooled to a temperature in the region of −78° C. 4.38 cm³ of borontribromide are added and the stirring is continued for 15 hours at atemperature in the region of 20° C. The solution is taken up withmethanol and is then concentrated to dryness under reduced pressure (2kPa). The residue is taken up with 20 cm³ of water and 20 cm³ ofdichloromethane. The organic phase is separated by settling out; theaqueous phase is washed with a saturated aqueous sodium bicarbonatesolution until a pH of 8-8.4 is obtained (pH meter), and then taken upwith dichloromethane. The organic phase is separated by settling out,and concentrated to dryness under reduced pressure (2 kPa). The whitepowder obtained is taken up with 0.4 cm³ of 12N hydrochloric acid and 5cm³ of dioxane. The mixture is stirred for 10 minutes and is thenconcentrated to dryness under reduced pressure (2 kPa). 198 mg of4-(3-hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride are obtained in the form of an ecru-colored powder.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50 (mt:1H); from 1.60 to 1.90 (mt: 5H); 2.94 (mt: 2H); from 3.30 to 3.55 (mt:4H); 4.40 (t, J=6.5 Hz: 2H); 6.55 (ddd, J=8-3 and 1.5 Hz: 1H); from 7.00to 7.15 (mt: 3H); 8.06 (s: 1H); from 9.10 to 9.40 (broad unresolvedpeak: 1H); from 9.90 to 10.10 (unresolved peak: 1H); from 10.30 to 10.45(unresolved peak: 1H). Mass spectrum (EI): m/z 287 (M+.), m/z 98 (basepeak).

EXAMPLE 45 4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

200 mg of 4-(4-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride are brought to pH 7 (Lyphan paper) with a 1N aqueoussodium hydroxide solution. The organic phase is extracted withdichloromethane and concentrated to dryness under reduced pressure (2kPa). The residue is taken up with 5 cm³ of dichloromethane. The stirredsolution is cooled to a temperature in the region of −78° C. 1.7 cm³ ofboron tribromide are added and the stirring is continued for 15 hours ata temperature in the region of 20° C. The solution is taken up with 20cm³ of ice-cold water and 10 cm³ of dichloromethane. The organic phaseis separated by settling out; the aqueous phase is washed withdichloromethane and then with a saturated aqueous sodium bicarbonatesolution until a pH of 8-8.4 (pH meter) is obtained, and then taken upwith dichloromethane. The organic phase is separated by settling out,and concentrated to dryness under reduced pressure (2 kPa). The whitepowder obtained is taken up with 300 μl of 12N hydrochloric acid and 5cm³ of dioxane. The mixture is stirred for 10 minutes and thenconcentrated to dryness under reduced pressure (2 kPa). 101 mg of4-(4-hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride are obtained in the form of an ecru-colored powder.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.25 to 1.50 (mt:1H); from 1.60 to 1.90 (mt: 5H); 2.92 (mt: 2H); from 3.30 to 3.50 (mt:4H); 4.38 (t, J=6.5 Hz: 2H); 6.75 (broad d, J=8.5 Hz: 2H); 7.45 (broadd, J=8.5 Hz: 2H); 7.85 (s: 1H); from 9.10 to 9.35 (broad unresolvedpeak: 1H); from 10.00 to 10.20 (unresolved peak: 1H); from 10.15 to10.30 (unresolved peak: 1H).

Mass spectrum (EI): m/z 287 (M+.), m/z 98 (base peak).

EXAMPLE 46 4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

7 cm³ of 1N hydrochloric diethyl ether are added to a solution of 640 mgof 1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazol-1-yl]ethyl}piperidine in20 cm³ of ethanol. After stirring for 30 min at a temperature in theregion of 20° C., the solution is evaporated to dryness under reducedpressure (2.7 kPa). The residue is taken up with 20 cm³ of ethanol. Thesolution obtained is introduced into an autoclave, and 87 mg ofpalladium-on-charcoal at 10% are added, and it is then placed underhydrogen (8 bar). After stirring for 8 h at a temperature in the regionof 30° C., the reaction medium is filtered over supercel and thefiltrate is evaporated. Diisopropyl ether is added to the residue,resulting in a suspension, which is heated at the reflux of the solventand filtered under hot conditions. The resulting solid is dried undervacuum (2.7 kPa) to give 400 mg of4-(4-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a white powder.

IR spectrum (KBr): 3052; 2933; 2655; 2559; 1578; 1569; 1518; 1501; 1453;1248; 1170; 1020; 837; 810; 652 and 528 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to 1.50 (mt:1H); from 1.60 to 1.90 (mt: 5H); from 2.80 to 3.05 (mt: 2H); 3.46 (mt:4H); 3.76 (s: 3H); 4.37 (broad t, J=6 Hz: 2H); 6.93 (d, J=8.5 Hz: 2H);7.57 (d, J=8.5 Hz: 2H); 7.92 (broad s: 1H); from 9.75 to 9.95 (broadunresolved peak: 1H); 10.32 (broad s: 1H).

The 1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazol-1-yl]ethyl}piperidinecan be prepared in the following way:

2 g of 4-methoxyphenylboronic acid, 2.85 g of potassium phosphate and750 mg of bis(triphenylphosphine)palladium chloride are added to astirred solution of 1.2 g of1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine in 60 cm³ of1,2-dimethoxyethane under an argon atmosphere. After heating for 15 h atthe reflux of the solvent, the reaction medium is evaporated underreduced pressure (2.7 kPa). Ethyl acetate and water are added to theresidue, which is filtered over supercel. The filtrate is separated bysettling out, and the organic phase is washed successively with water, asaturated aqueous hydrogen carbonate solution, and a saturated aqueoussodium chloride solution; it is dried over magnesium sulfate, filteredand evaporated under reduced pressure (2.7 kPa). The brown oil obtained(3.6 g) is purified by flash chromatography on alumina CTB1 under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 byvolume)]. After concentration of the fractions under reduced pressure(2.7 kPa), 700 mg of1-{2-[3-benzyloxy-4-(4-methoxyphenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a yellow oil.

Mass spectrum (EI): m/z 391 (M^(+.)), m/z 280 [(M-C₇H₁₃N)^(+.)], m/z 111(C₇H₁₃N^(+.)), m/z 98 (C₆H₁₂N⁺), m/z 91 (C₇H₇ ⁺)

EXAMPLE 47 4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

3.5 cm³ of 12N hydrochloric acid are added to a stirred solution of 400mg of 1-{2-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]ethyl}piperidinein 3.5 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue isdried under vacuum (2.7 kPa) at 45° C. for 1 h, and is triturated indiisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 350 mg of4-(3-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a white solid.

IR spectrum (KBr): 2951; 2647; 2540; 1619; 1586; 1530; 1456; 1267; 1178;882; 785; 687 and 523 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with the addition of a few dropsof CD₃COOD d4, δ in ppm): 1.42 (mt: 1H); from 1.60 to 1.90 (mt: 5H);2.95 (mt: 2H); from 3.40 to 3.55 (mt: 2H); 3.50 (t, J=6.5 Hz: 2H); 4.39(t, J=6.5 Hz: 2H); 6.95 (tdd, J=7.5-3 and 1 Hz: 1H); from 7.30 to 7.50(mt: 3H); 8.09 (s: 1H).

The 1-{2-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]-ethyl}piperidinecan be prepared in the following way:

1.15 g of 3-fluorophenylboronic acid, 4.1 cm³ of a 2N aqueous potassiumcarbonate solution and 475 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution, under an argon atmosphere, of 1 g of1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine in a mixture of20 cm³ of toluene and of 5 cm³ of ethanol. After heating at the refluxof the solvent for 3 h and at a temperature in the region of 20° C. for15 h, ethyl acetate and water are added to the reaction medium, which isfiltered over supercel. The filtrate is separated by settling out, andthe organic phase is then washed successively with 2 times water and asaturated aqueous sodium chloride solution; it is dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa). Thebrown oil obtained (2.1 g) is purifed by flash chromatography on silicaunder an argon pressure (50 kPa) [eluent: ethyl acetate]. Afterconcentration of the fractions under reduced pressure, 400 mg of1-{2-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a yellow oil.

IR spectrum (CCl₄): 2939; 2854; 2802; 1617; 1586; 1509; 1463; 1432;1359; 1272; 1187; 1169; 1160; 1043; 883; 695 and 687 cm⁻¹.

EXAMPLE 481-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-1H-pyrazol-3-oldihydrochloride

5 cm³ of 12N hydrochloric acid are added to a stirred solution of 470 mgof1-{2-[3-benzyloxy-4-(3-trifluoromethylphenyl)pyrazol-1-yl]ethyl}piperidinein 5 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue isdried under vacuum (2.7 kPa) at 45° C. for 1 h, and is then trituratedin diisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 350 mg of1-(2-piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-1H-pyrazol-3-oldihydrochloride in the form of a pale yellow solid.

IR spectrum (KBr): 2955; 2629; 2533; 1619; 1533; 1325; 1188; 1170; 1117;1076; 800; 696 and 688 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.94 (mt: 2H); from 3.30 to 3.55 (mt: 4H); 4.43(t, J=6.5 Hz: 2H); 7.50 (broad d, J=7.5 Hz: 1H); 7.59 (t, J=7.5 Hz: 1H);7.95 (broad d, J=7.5 Hz: 1H); 8.01 (broad s: 1H); 8.22 (s: 1H); 10.24(unresolved peak: 1H); from 10.60 to 10.90 (broad unresolved peak: 1H).

The1-{2-[3-benzyloxy-4-(3-trifluoromethylphenyl)-pyrazol-1-yl]ethyl}piperidinecan be prepared in the following way:

1.58 g of 3-trifluoromethylphenylboronic acid, 4.1 cm³ of a 2N aqueouspotassium carbonate solution and 475 mg oftetrakis(triphenylphosphine)palladium are added to a stirred solution,under an argon atmosphere, of 1 g of1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine in a mixture of20 cm³ of toluene and of 5 cm³ of ethanol. After heating at the refluxof the solvent for 3 h, the reaction medium is evaporated under reducedpressure (2.7 kPa). Ethyl acetate and water are added to the residue,which is filtered over supercel. The filtrate is separated by settlingout, and the organic phase is then washed successively with 2 timeswater and a saturated aqueous sodium chloride solution; it is dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa). The brown oil obtained (3 g) is purified by flash chromatographyon silica under an argon pressure (50 kPa) [eluent: ethylacetate/methanol (95/5 by volume)]. After concentration of the fractionsunder reduced pressure (2.7 kPa), a residue is obtained which is takenup with ethyl acetate. The solution is treated with carbon black,filtered and evaporated under reduced pressure (2.7 kPa) to give 470 mgof1-{2-[3-benzyloxy-4-(3-trifluoromethylphenyl)pyrazol-1-yl]ethyl}piperidinein the form of an orange-colored oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.30 to 1.55 (mt:6H); 2.40 (unresolved peak: 4H); 2.70 (unresolved peak: 2H); 4.10(unresolved peak: 2H); 5.34 (s: 2H); from 7.30 to 7.55 (mt: 6H); 7.58(t, J=7.5 Hz: 1H); 7.92 (broad d, J=7.5 Hz: 1H); 8.03 (broad s: 1H);8.25 (s: 1H).

EXAMPLE 49 1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-3-oldihydrochloride

7 cm³ of 12N hydrochloric acid are added to a stirred solution of 720 mgof 3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine in7 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 hat a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with ethanol, and the mixture is then evaporated to drynessunder vacuum (2.7 kPa). The operation is repeated twice, and the solidis then dried under vacuum (2.7 kPa) at 45° C. for 1 h, and istriturated in acetone. The precipitate formed is filtered off and driedunder vacuum (2.7 kPa) to give 190 mg of1-(2-piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-3-ol dihydrochloridein the form of a white solid.

IR spectrum (KBr): 2970; 2434; 2931; 1601; 1551; 1460; 1307; 1178; 825;691 and 624 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.94 (mt: 3H); from 3.25 to 3.65 (mt: 3H); 4.50(t, J=6.5 Hz: 2H); 7.88 (broad dd, J=8 and 5 Hz: 1H); 8.39 (s: 1H); 8.55(broad d, J=8 Hz: 1H); 8.60 (broad d, J=5 Hz: 1H); 9.02 (broad d, J=1.5Hz: 1H); 10.60 (unresolved peak: 1H); 11.20 (unresolved peak: 1H).

The 3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridinecan be prepared in the following way:

580 mg of 3-diethylboranylpyridine, 690 mg of sodium carbonate dissolvedin 20 cm³ of water, and 390 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution of 950 mg of1-[2-(3-benzyloxy-4-bromopyrazol-1-yl)ethyl]piperidine in 100 cm³ ofdioxane and under an argon atmosphere. After heating at the reflux ofthe solvent for 3 h, the reaction medium is cooled to a temperature inthe region of 20° C., ethyl acetate and water are added, and the mixtureis filtered over supercel. The filtrate is separated by settling out,and the organic phase is then washed with water and a saturated aqueoussodium chloride solution; it is dried over magnesium sulfate, filteredand evaporated under reduced pressure (2.7 kPa). The brown oil obtained(2 g) is purified by flash chromatography on alumina CTB1 under an argonpressure (50 kPa) [eluent: cyclohexane/ethyl acetate (97/3 by volume),then ethyl acetate]. After concentration of the fractions under reducedpressure (2.7 kPa), a residue is obtained which is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent: ethylacetate/methanol (90/10 by volume)]. After concentration of thefractions under reduced pressure (2.7 kPa), 220 mg of3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine areobtained in the form of a yellow oil.

IR spectrum (CCl₄): 2940; 2854; 2801; 1599; 1575; 1505; 1453; 1362;1167; 1020; 708 and 702 cm⁻¹.

EXAMPLE 50 4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

3.5 cm³ of 12N hydrochloric acid are added to a stirred solution of 470mg of 1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]ethyl}piperidinein 3.5 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction mixture isevaporated to dryness under reduced pressure (2.7 kPa). The residue isdried under vacuum (2.7 kPa) at 45° C. for 2 h, and is then trituratedin diisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 430 mg of4-(4-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a white solid.

IR spectrum (KBr): 2952; 2640; 2534; 1607; 1578; 1552; 1521; 1455; 1191;1093; 1011; 830; 818 and 516 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.39 (mt: 1H); from1.60 to 1.85 (mt: 5H); 2.92 (mt: 2H); from 3.35 to 3.45 (mt: 2H); 3.46(broad t, J=6.5 Hz: 2H); 4.42 (t, J=6.5 Hz: 2H); 7.39 (dmt, J=8.5 Hz:2H); 7.67 (dmt, J=8.5 Hz: 2H); 8.08 (s: 1H); 10.39 (unresolved peak:1H).

The 1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-ethyl}piperidinecan be prepared in the following way:

A solution of 440 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole in 20cm³ of dimethylformamide is added to a suspension of 132 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 15 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred for 30 min at atemperature in the region of 20° C., and 400 mg of1-(2-chloroethyl)piperidine hydrochloride are then added. The reactionmedium is stirred for 15 h at a temperature in the region of 20° C., andis then poured into water. The aqueous phase is extracted twice withethyl acetate. The organic phases are pooled, washed successively withwater and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give a pale yellow oil, which is purified by flashchromatography on alumina CTB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (95/5, then 90/10 by volume)]. Afterconcentration of the fractions under reduced pressure, 470 mg of1-{2-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a pale yellow oil.

IR spectrum (CCl₄): 2938; 1574; 1509; 1482; 1452; 1358; 1171; 1094;1037; 1014; 834; 695 and 511 cm⁻¹.

The 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole can be prepared in thefollowing way:

2 cm³ of 1N solution of tetrabutylammonium fluoride in tetrahydrofuranare added to a stirred solution, under an argon atmosphere, of 800 mg of3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 20cm³ of tetrahydrofuran. After heating at the reflux of the solvent for 2h, 0.5 cm³ of 1N solution of tetrabutylammonium fluoride intetrahydrofuran is added to the reaction medium, which is maintained at60° C. for 15 h. A further 0.5 cm³ of 1N solution of tetrabutylammoniumfluoride in tetrahydrofuran is added to the solution, which is heated atthe reflux of the solvent for a further 2 h. The reaction medium is thencooled to a temperature in the region of 20° C. and evaporated underreduced pressure (2.7 kPa). Ethyl acetate is added to the residue, andthe organic phase is washed successively with two times water and asaturated aqueous sodium chloride solution; it is dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa). Theresulting yellow solid is purified by flash chromatography on silicaunder an argon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate(80/20 by volume), then ethyl acetate]. After concentration of thefractions under reduced pressure (2.7 kPa), 440 mg of3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole are obtained in the form of awhite solid.

Mass spectrum (EI): m/z 284 (M^(+.)), m/z 206 [(M-C₆H₆)^(+.)], m/z 91(C₇H₇ ⁺).

The 3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

1.15 g of 4-chlorophenylboronic acid, 3.6 cm³ of a 2N aqueous potassiumcarbonate solution and 360 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution, under an argon atmosphere, of 1.1 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm³ oftoluene to which 5 cm³ of ethanol have been added. After heating at thereflux of the solvent for 15 h, the reaction medium is evaporated underreduced pressure (2.7 kPa). Ethyl acetate, water and carbon black areadded to the residue, which is filtered over supercel. The filtrate isseparated by settling out, and the organic phase is then washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa). The brown oil obtained (2.6g) is purified by flash chromatography on silica under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. Afterconcentration of the fractions under reduced pressure (2.7 kPa), 800 mgof 3-benzyloxy-4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole areobtained in the form of an orange-colored solid. Mass spectrum (CI): m/z456 (MNH₄ ⁺), m/z 439 (MH⁺).

EXAMPLE 51 4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

5 cm³ of 12N hydrochloric acid are added to a stirred solution of 550 mgof 1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]ethyl}piperidine in5 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 hat a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue isdried under vacuum (2.7 kPa) at 45° C. for 2 h, and is then trituratedin diisopropyl ether. The precipitate formed is filtered and dried undervacuum (2.7 kPa) to give 460 mg of4-(3-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a white solid.

IR spectrum (KBr): 2951; 2637; 2436; 1394; 1603; 1565; 1521; 1454; 1180;778 and 689 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.40 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.95 (mt: 2H); from 3.35 to 3.55 (mt: 4H); 4.40(t, J=6.5 Hz: 2H); 7.20 (dmt, J=8 Hz: 1H); 7.37 (t, J=8 Hz: 1H); 7.62(broad d, J=8 Hz: 1H); 7.73 (t, J=2 Hz: 1H); 8.14 (s: 1H); 9.90(unresolved peak: 1H); 10.69 (unresolved peak: 1H).

The 1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-ethyl}piperidinecan be prepared in the following way:

A solution of 500 mg of 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole in 20cm³ of dimethylformamide is added to a suspension of 142 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 15 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred for 30 min at atemperature in the region of 20° C., and a solution of 500 mg of1-(2-chloroethyl)piperidine hydrochloride is then added. The reactionmedium is stirred at a temperature in the region of 20° C. for 15 h, andis then poured into water. The aqueous phase is extracted twice withethyl acetate. The organic phases are pooled, washed successively withwater and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa) to give a yellow oil which is purified by flash chromatography onalumina CTB1 under an argon pressure (50 kPa) [eluent: cyclohexane/ethylacetate (95/5 by volume)]. After concentration of the fractions underreduced pressure, 550 mg of1-{2-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a yellow oil.

IR spectrum (CCl₄): 2938; 2853; 1603; 1574; 1507; 1452; 1357; 1260;1174; 1046; 997; 695 and 687 cm⁻¹.

The 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole can be prepared in thefollowing way:

4.6 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a stirred solution, under an argonatmosphere, of 810 mg of3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 20cm³ of tetrahydrofuran. After heating at the reflux of the solvent for15 h, the reaction medium is evaporated under reduced pressure (2.7 kPa)and ethyl acetate is added to the residue. The organic phase is washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa). The resulting oil (0.7 g)is purified by flash chromatography on silica under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Afterconcentration of the fractions under reduced pressure (2.7 kPa), 500 mgof 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole are obtained in the formof a white solid.

IR spectrum (KBr): 3148; 2957; 1601; 1505; 1446; 1422; 1355; 1237; 1229;1046; 785; 729; 682 and 597 cm⁻¹.

The 3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

1.03 g of 3-chlorophenylboronic acid, 3.3 cm³ of a 2N aqueous potassiumcarbonate solution and 380 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution, under an argon atmosphere, of 1 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm³ oftoluene to which 5 cm³ of ethanol have been added. After heating at thereflux of the solvent for 2.5 h, the reaction medium is evaporated underreduced pressure (2.7 kPa). Ethyl acetate, water and carbon black areadded to the residue, which is filtered over supercel. The filtrate isseparated by settling out, and the organic phase is then washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa). The orange-colored oilobtained (2 g) is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (97/3 byvolume)]. After concentration of the fractions under reduced pressure(2.7 kPa), 810 mg of3-benzyloxy-4-(3-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole areobtained in the form of a yellow solid.

IR spectrum (KBr): 3098; 1604; 1508; 1372; 1357; 1189; 1180; 1094; 991;790; 672; 586; 554 and 536 cm⁻¹.

EXAMPLE 52 4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride

7 cm³ of 12N hydrochloric acid are added to a stirred solution of 800 mgof 1-{2-[3-benzyloxy-4-(2-fluorophenyl)pyrazol-1-yl]ethyl}piperidine in10 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 hat a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The crude istaken up with ethanol, and the mixture is then evaporated to drynessunder reduced pressure (2.7 kPa); the operation is repeated twice. Theresidue is triturated in diisopropyl ether, and the precipitate formedis filtered off, and is then dissolved under hot conditions in ethanol.The crystals which have appeared after cooling of the solution in an icebath are filtered and dried under vacuum (2.7 kPa) to give 470 mg of4-(2-fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-oldihydrochloride in the form of a white solid.

IR spectrum (KBr): 2947; 2621; 2540; 1620; 1538; 1463; 1231; 1186; 1093;970; 761 and 656 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.41 (mt: 1H); from1.60 to 1.90 (mt: 5H); 2.94 (mt: 2H); from 3.35 to 3.55 (mt: 4H); 4.46(broad t, J=6.5 Hz: 2H); from 7.15 to 7.30 (mt: 3H); from 7.90 to 8.05(mt: 2H); 10.15 (unresolved peak: 1H); 10.65 (broad s: 1H).

The 1-{2-[3-benzyloxy-4-(2-fluorophenyl)pyrazol-1-yl]-ethyl}piperidinecan be prepared in the following way:

A solution of 650 mg of 3-benzyloxy-4-(2-fluorophenyl)-1H-pyrazole in 20cm³ of dimethylformamide is added to a suspension of 200 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 10 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred at a temperature inthe region of 20° C. for 30 min, and 625 mg of1-(2-chloroethyl)piperidine hydrochloride are added. The reaction mediumis stirred for 15 h at a temperature in the region of 20° C., and isthen poured into 100 cm³ of water. The aqueous phase is extracted twicewith ethyl acetate. The organic phases are pooled, washed successivelywith two times water and a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and evaporated under reducedpressure (2.7 kPa) to give a yellow oil (1.1 g), which is purified byflash chromatography on alumina CTB1 under an argon pressure (50 kPa)[eluent: cyclohexane/ethyl acetate (95/5 by volume)]. Afterconcentration of the fractions under reduced pressure, 800 mg of1-{2-[3-benzyloxy-4-(2-fluorophenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a yellow oil.

IR spectrum (CCl₄): 2938; 2855; 2801; 1572; 1512; 1486; 1358; 1175;1044; 1027 and 696 cm⁻¹.

The 3-benzyloxy-4-(2-fluorophenyl)-1H-pyrazole can be prepared in thefollowing way: 7.4 cm³ of a 1N solution of tetrabutylammonium fluoridein tetrahydrofuran are added to a stirred solution, under an argonatmosphere, of 1.25 g of3-benzyloxy-4-(2-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30cm³ of tetrahydrofuran. After heating at the reflux of the solvent for15 h, the reaction medium is evaporated under reduced pressure (2.7 kPa)and ethyl acetate is added to the residue. The organic phase is washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa). The resulting oil (0.92 g)is purified by flash chromatography on silica under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Afterconcentration of the fractions under reduced pressure (2.7 kPa), 650 mgof 3-benzyloxy-4-(2-fluorophenyl)-1H-pyrazole are obtained in the formof a white solid.

IR spectrum (KBr): 3161; 2954; 2691; 1572; 1474; 1440; 1353; 1264; 1045;1036; 1027; 759; 729 and 654 cm⁻¹.

The 3-benzyloxy-4-(2-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

1.4 g of 2-fluorophenylboronic acid, 5 cm³ of a 2N aqueous potassiumcarbonate solution and 500 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution, under an argon atmosphere, of 1.5 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in a mixture of 20cm³ of toluene and of 5 cm³ of ethanol. After heating at the reflux ofthe solvent for 3 h, the reaction medium is cooled to a temperature inthe region of 20° C. and evaporated under reduced pressure (2.7 kPa).Ethyl acetate, water and carbon black are added to the residue, which isfiltered over supercel. The filtrate is separated by settling out, andthe organic phase is then washed successively with two times water and asaturated aqueous sodium chloride solution; it is dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa). Theorange-colored oil obtained (2 g) is purified by flash chromatography onsilica under an argon pressure (50 kPa) [eluent: cyclohexane/ethylacetate (95/5 by volume)]. After concentration of the fractions underreduced pressure (2.7 kPa), 1.25 g of3-benzyloxy-4-(2-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole areobtained in the form of an orange-colored oil. Mass spectrum (EI): m/z422 (M^(+.)), m/z 267 [(M-C₇H₇O2S)⁺], m/z 91 (C₇H₇ ^(+.)).

EXAMPLE 53 4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

5 cm³ of 12N hydrochloric acid are added to a stirred solution of 570 mgof 1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazol-1-yl]ethyl}piperidine in7 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 hat a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with ethanol, and the mixture is then evaporated to drynessunder vacuum (2.7 kPa). The operation is repeated twice, and the lacquerobtained is then dried under vacuum (2.7 kPa) at 45° C. for 30 min, andis then dissolved under hot conditions in ethanol. The crystals formedafter cooling of the solution in an ice bath are filtered and driedunder vacuum (2.7 kPa) to give 380 mg of4-(2-chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride in the form of a white solid.

IR spectrum (KBr): 3097; 2939; 2674; 2545; 1579; 1517; 1439; 1224; 1171;935; 758 and 653 cm⁻¹.

¹H NMR spectrum (200 MHz, (CD₃)₂SO d6 with the addition of a few dropsof CD₃COOD d4, at a temperature of 363 K, δ in ppm): 1.60 (mt: 2H); 1.81(mt: 4H); 3.20 (unresolved peak: 4H); 3.49 (broad t, J=6.5 Hz: 2H); 4.42(broad t, J=6.5 Hz: 2H); 7.26 (broad t, J=7.5 Hz: 1H); 7.35 (broad t,J=7.5 Hz: 1H); 7.48 (broad d, J=7.5 Hz: 1H); 7.66 (broad d, J=7.5 Hz:1H); 7.93 (broad s: 1H).

The 1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazol-1-yl]-ethyl}piperidinecan be prepared in the following way:

A solution of 500 mg of 3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole in 20cm³ of dimethylformamide is added to a suspension of 140 mg of sodiumhydride (at 75% in liquid petroleum jelly) in 10 cm³ ofdimethylformamide under an argon atmosphere and with stirring. Afterheating at 50° C. for 30 min, the mixture is stirred at a temperature inthe region of 20° C. for 30 min, and 453 mg of1-(2-chloroethyl)piperidine hydrochloride are then added. The reactionmedium is stirred at a temperature in the region of 20° C. for 15 h, andis then poured into 100 cm³ of water. The aqueous phase is extractedtwice with ethyl acetate. The organic phases are pooled, washedsuccessively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa) to give a yellow oil (0.8 g), which ispurified by flash chromatography on alumina CTB1 under an argon pressure(50 kPa) [eluent: cyclohexane/ethyl acetate (95/5 by volume)]. Afterconcentration of the fractions under reduced pressure, 570 mg of1-{2-[3-benzyloxy-4-(2-chlorophenyl)pyrazol-1-yl]ethyl}piperidine areobtained in the form of a colorless oil.

IR spectrum (CCl₄): 2938; 2853; 2801; 1573; 1506; 1456; 1450; 1357;1174; 1125; 1036; 1025; 716 and 695 cm⁻¹.

The 3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole can be prepared in thefollowing way:

6.9 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a stirred solution, under an argonatmosphere, of 1.2 g of3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30cm³ of tetrahydrofuran. After heating at the reflux of the solvent for15 h, the reaction medium is evaporated under reduced pressure (2.7 kPa)and ethyl acetate is added to the residue. The organic phase is washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa). The resulting oil istriturated in pentane. The precipitate formed is filtered off and driedunder reduced pressure to give 500 mg of3-benzyloxy-4-(2-chlorophenyl)-1H-pyrazole in the form of a yellowsolid. Mass spectrum (EI): m/z 284 (M^(+.)), m/z 249 [(M-Cl)⁺], m/z 91(C₇H₇ ⁺).

The 3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

1.55 g of 2-chlorophenylboronic acid, 5 cm³ of a 2N aqueous potassiumcarbonate solution and 500 mg of tetrakis(triphenylphosphine)palladiumare added to a stirred solution, under an argon atmosphere, of 1.5 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 20 cm³ oftoluene to which 5 cm³ of ethanol have been added. After heating at thereflux of the solvent for 5 h, the reaction medium is evaporated underreduced pressure (2.7 kPa). Ethyl acetate, water and carbon black areadded to the residue, which is filtered over supercel. The filtrate isseparated by settling out, and the organic phase is washed successivelywith two times water and a saturated aqueous sodium chloride solution;it is dried over magnesium sulfate, filtered and evaporated underreduced pressure (2.7 kPa). The orange-colored oil obtained is purifiedby flash chromatography on silica under an argon pressure (50 kPa)[eluent: cyclohexane/ethyl acetate (95/5 by volume)]. Afterconcentration of the fractions under reduced pressure (2.7 kPa), 1.2 gof 3-benzyloxy-4-(2-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole areobtained in the form of an orange-colored oil. Mass spectrum (EI): m/z438 (M^(+.)), m/z 283 [(M-C₇H₇SO2)⁺], m/z 91 (C₇H₇ ⁺).

EXAMPLE 541-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-oldihydrochloride

2.5 cm³ of 12N hydrochloric acid are added to a stirred solution of 220mg of3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 5 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with ethanol, and the mixture is then evaporated to drynessunder vacuum (2.7 kPa). The operation is repeated twice, and the foamobtained is then triturated in diisopropyl ether. The precipitate formedis filtered off and dried under vacuum (2.7 kPa) to give 170 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-oldihydrochloride in the form of a white solid.

IR spectrum (KBr): 3052; 2926; 2793; 2559; 1606; 1576; 1520; 1486; 1454;1195; 1167; 1090; 1010; 827; 626 and 515 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 2.05 (mt:4H); 2.42 (mt: 1H); from 3.15 to 3.50 (mt: 4H); from 3.70 to 3.85 (mt:2H); 4.67 (mt: 1H); 7.40 (broad d, J=8 Hz: 2H); 7.71 (broad d, J=8 Hz:2H); 8.35 (s: 1H); from 10.50 to 10.70 (broad unresolved peak: 1H);10.73 (unresolved peak: 1H).

The3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

500 mg of potassium tert-butoxide, followed by a solution of 660 mg oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm³ ofdimethylformamide, are added to a stirred solution, under an argonatmosphere, of 500 mg of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole in20 cm³ of dimethylformamide. After heating at 110° C. for 15 h, thereaction medium is poured into 100 cm³ of water and the mixture isextracted twice with ethyl acetate. The organic phases are washedsuccessively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa). The orange-colored oil (650 mg)obtained is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: ethyl acetate, then dichloromethane/methanol(80/20 by volume)]. After concentration of the fractions under reducedpressure (2.7 kPa), 220 mg of3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneare obtained in the form of a pale yellow oil.

IR spectrum (CCl₄): 3035; 2941; 2873; 1605; 1574; 1508; 1481; 1454;1165; 1095; 1014; 834; 695 and 513 cm⁻¹.

EXAMPLE 551-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazol-3-olhydrochloride

3 cm³ of 12N hydrochloric acid are added to a stirred solution of 270 mgof3-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 6 cm³ of ethanol. After 7 h at the reflux of the solvent, thereaction medium is evaporated to dryness under reduced pressure (2.7kPa). The residue is taken up with ethanol, and the mixture is thenevaporated to dryness under vacuum (2.7 kPa). The operation is repeatedtwice, and the foam obtained is then triturated in diisopropyl ether.The precipitate formed is filtered off and dried under vacuum (2.7 kPa)to give 180 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(3-chlorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a white solid.

IR spectrum (KBr): 2931; 2801; 2660; 2557; 1599; 1563; 1517; 1459; 1425;1165; 1095; 950; 891; 840; 788; 685; 627 and 440 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 2.05 (mt:4H); 2.43 (mt: 1H); from 3.15 to 3.45 (mt: 4H); from 3.70 to 3.85 (mt:2H); 4.67 (mt: 1H); 7.20 (ddd, J=8-2 and 1 Hz: 1H); 7.38 (t, J=8 Hz:1H); 7.67 (broad d, J=8 Hz: 1H); 7.75 (t, J=2 Hz: 1H); 8.31 (s: 1H);from 10.30 to 10.60 (broad unresolved peak: 1H); 10.68 (broad s: 1H).

The3-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

560 mg of potassium tert-butoxide, followed by a solution of 740 mg oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm³ ofdimethylformamide, are added to a stirred solution, under an argonatmosphere, of 570 mg of 3-benzyloxy-4-(3-chlorophenyl)-1H-pyrazole in20 cm³ of dimethylformamide. After heating at 110° C. for 15 h, thereaction medium is poured into 100 cm³ of water and the mixture isextracted twice with ethyl acetate. The organic phases are washedsuccessively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa). The orange-colored oil (800 mg)obtained is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: ethyl acetate/methanol (90/10 by volume),then dichloromethane/methanol (80/20 by volume)]. After concentration ofthe fractions under reduced pressure (2.7 kPa), 270 mg of3-[3-benzyloxy-4-(3-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneare obtained in the form of a pale yellow oil.

IR spectrum (CCl₄): 3034; 1602; 1574; 1507; 1454; 1356; 1176; 1097;1048; 695 and 687 cm⁻¹.

EXAMPLE 561-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-pyrazol-3-olhydrochloride

2 cm³ of 12N hydrochloric acid are added to a stirred solution of 85 mgof3-[3-benzyloxy-4-(3-fluorophenyl)-pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 4 cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with ethanol, and the mixture is then evaporated to drynessunder vacuum (2.7 kPa). The operation is repeated twice, and the foamobtained is then triturated in diisopropyl ether. The precipitate formedis filtered off and dried under vacuum (2.7 kPa) to give 63 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(3-fluorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a beige solid.

IR spectrum (KBr): 2932; 2765; 2663; 2577; 1617; 1586; 1521; 1457; 1436;1265; 1180; 1165; 876; 783; 666; 625 and 521 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.65 to 2.05 (mt:4H); 2.43 (mt: 1H); from 3.10 to 3.50 (mt: 4H); 3.78 (broad d, J=7 Hz:2H); 4.67 (mt: 1H); 6.96 (broad double doublet of a triplet, J=8 and 2.5Hz: 1H); from 7.25 to 7.55 (mt: 3H); 8.28 (s: 1H); 10.12 (unresolvedpeak: 1H); 10.65 (s: 1H).

The3-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

260 mg of potassium tert-butoxide, folowed by a solution of 400 mg oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm³ ofdimethylformamide, are added to a stirred solution, under an argonatmosphere, of 250 mg of 3-benzyloxy-4-(3-fluorophenyl)-1H-pyrazole in20 cm³ of dimethylformamide. After heating at 110° C. for 15 h, thereaction medium is poured into 100 cm³ of water, and the mixture isextracted twice with ethyl acetate. The organic phases are washedsuccessively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa). The orange-colored oil (345 mg)obtained is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 by volume),then dichloromethane/methanol (80/20 by volume)]. After concentration ofthe fractions under reduced pressure (2.7 kPa), 270 mg of3-[3-benzyloxy-4-(3-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneare obtained in the form of a pale yellow oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 0.80 (mt: 1H); 1.53(mt: 1H); 1.67 (mt: 2H); 2.09 (mt: 1H); from 2.60 to 2.80 (mt: 3H); 2.98(mt: 1H); 3.21 (ddd, J=14-10 and 1.5 Hz: 1H); 3.37 (broad dd, J=14 and5.5 Hz: 1H); 4.25 (mt: 1H); 5.35 (s: 2H); 6.95 (broad double doublet ofa triplet, J=8 and 2.5 Hz: 1H); from 7.25 to 7.55 (mt: 8H); 8.31 (s:1H).

EXAMPLE 57 1-(1-Methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride

A few drops of methanol are added to a mixture of 165 mg of1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol in 2 cm³ of ethylacetate, in order to solubilize the medium, which is cooled to 0° C.before the addition of 5 cm³ of 3M solution of hydrochloric acid inethyl acetate. The reaction medium is stirred for 5 min at 0° C., leftto return to a temperature in the region of 20° C., and then stirredagain at this temperature for 20 min before being concentrated underreduced pressure (2.7 kPa). The crude product is dried on a vane pump(10⁻³ kPa) to give 160 mg of1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol hydrochloride inthe form of a very hygroscopic solid. LCMS (electrospray): m/z 244(MH⁺).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 at 80° C., δ in ppm): from 2.30 to2.65 (m: 2H); 2.91 (s: 3H); from 3.10 to 4.00 (m: 4H); 5.03 (m: 1H);7.14 (t, J=7.5 Hz: 1H); 7.32 (t, J=7.5 Hz: 2H); 7.65 (t, J=7.5 Hz: 2H);8.00 (s: 1H).

The 1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol can be preparedin the following way:

7.55 cm³ of a 4M aqueous hydrochloric acid solution are added to asolution of 505 mg of3-benzyloxy-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole in 3.53 cm³of ethanol. The reaction medium is stirred at reflux for 8 h and is thenconcentrated under reduced pressure (2.7 kPa). The violet oil obtainedis taken up three times with diethyl ether, evaporated to dryness underreduced pressure (2.7 kPa), taken up three times with isopropanol andconcentrated under reduced pressure and, finally, taken up three timeswith dichloromethane to give a congealed oil which, after drying on avane pump (10⁻³ kPa), gives 524 mg of a solid. The residue is purifiedby chromatography on a column of 30 g of silica (irregular 15-40 μmMerck) [eluent: dichloromethane/methanol/39% ammonium hydroxide(95/5/0.4 by volume); flow rate: 8 cm³/min; detection: 250 nm]. Afterconcentration of the fractions under reduced pressure, 279 mg of1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol are obtained in theform of a colorless amorphous solid. LCMS (electrospray): m/z 334 (MH⁺).

The 3-benzyloxy-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole can beobtained in the following way: 123 mg of sodium hydride (at 50% in oil)are added to a solution of 428 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in8.5 cm³ of dimethylformamide, stirred under a nitrogen atmosphere and at0° C. After stirring at a temperature in the region of 20° C. for 30min, a solution of 398 mg of methanesulfonic acid(1-methylpyrrolidin-3-yl) ester in 5.6 cm³ of dimethylformamide isadded. The reaction medium is stirred for 1 h at 80° C. and then pouredinto a water/ethyl acetate mixture. After stirring for 5 min, the mediumis separated by settling out and the aqueous phase is extracted threetimes with ethyl acetate. The organic phases are pooled, washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered through an Iena filter and evaporated under reducedpressure (2.7 kPa) to give 657 mg of an oil which is purified bychromatography on a column of 30 g of silica (irregular 15-40 μm Merck)[eluent: dichloromethane/methanol (97/3 by volume); flow rate: 8cm³/min; detection: 250 nm]. After concentration of the fractions underreduced pressure, 511 mg of3-benzyloxy-1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-pyrazole areobtained in the form of a colorless amorphous solid. LCMS(electrospray): 334 (MH⁺).

The methanesulfonic acid (1-methylpyrrolidin-3-yl) ester can be preparedin the following way:

A solution of 0.33 cm³ of methanesulfonyl chloride in 7.07 cm³ ofdichloromethane is added dropwise to a stirred solution of 0.39 cm³ of1-methyl-3-hydroxypyrrolidine and 0.62 cm³ of triethylamine in 7.7 cm³of dichloromethane under a nitrogen atmosphere, at −10° C. The reactionmedium is stirred at −10° C. for 5 min and then at a temperature in theregion of 20° C. for 2 h, before being concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is taken up with waterand ethyl acetate. The solution is stirred for 5 min and is thenseparated by settling out. The aqueous phase is extracted three timeswith ethyl acetate. The organic phases are pooled, washed successivelywith a 5% aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered andevaporated under reduced pressure (2.7 kPa) to give 399 mg ofmethanesulfonic acid (1-methylpyrrolidin-3-yl) ester in the form of acolorless oil. LCMS (electrospray): m/z 180 (MH⁺), m/z 84[MH⁺−(SO₂CH₃)].

EXAMPLE 58 1-[2-(1-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride

A suspension of 200 mg of3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazoleand of the tip of a spatula of palladium-on-charcoal at 10% in 6 cm³ ofethanol is hydrogenated at a temperature in the region of 20° C. underan atmosphere of 1600 mbar for 3 h 30 min. The reaction medium is takenup with a dichloromethane/methanol mixture and filtered over clarcel.The filtrate is concentrated to dryness under reduced pressure (2.7 kPa)to give 120 mg of1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol in theform of a crystallized product. A second batch of 100 mg of1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol isprepared according to the same process, but using 140 mg of3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazole.

A solution of 160 mg of1-[2-(1-methylpyrrolidin-2-yl)-ethyl]-4-phenyl-1H-pyrazol-3-ol in 5 cm³of methanol is acidified (pH 1) with a solution of hydrochloric acid inmethanol. The reaction medium is stirred for 10 min at a temperature inthe region of 20° C., and is then concentrated under reduced pressure(2.7 kPa) and placed in a freezer overnight. The residue is taken upwith acetonitrile, spin-filtered, and then washed with acetonitrilebefore being dried under vacuum to give 160 mg of1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-oldihydrochloride in the form of a hygroscopic amorphous white powder.LCMS (electrospray): m/z 272 (MH⁺).

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): 1.65 (m: 1H); 1.92 (m:2H); 2.09 (m: 1H); 2.21 (m: 1H); 2.41 (m: 1H); 2.77 (d, J=5.0 Hz: 3H);3.01 (m: 1H); 3.15 (m: 1H); 3.52 (m: 1H); 4.04 (dt, J=14.0 and 6.5 Hz:1H); 4.07 (dt, J=14.0 and 6.5 Hz: 1H); 7.11 (t, J=7.5 Hz: 1H); 7.31 (t,J=7.5 Hz: 2H); 7.63 (t, J=7.5 Hz: 2H); 7.98 (s: 1H); 10.70 (s: 1H).

The3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazolecan be prepared in the following way:

82 mg of sodium hydride (at 50% in oil) are added, in three portions, toa solution of 425 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 2.5 cm³ ofdimethylformamide. Once no more gas is being given off, the reactionmedium is stirred at a temperature in the region of 20° C. for a further15 minutes before the addition of a solution of 250 mg of1-methyl-2-(2-chloroethyl)pyrrolidine in 0.5 cm³ of dimethylformamide.The reaction medium is stirred at a temperature in the region of 20° C.for 1 h, and then at 50° C. for 3 h, before being poured into water. Thesolution is extracted with ethyl acetate. The organic phase is washedwith a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa) togive 580 mg of a crude product which is purified by chromatography on 25g of silica gel [eluent: dichloromethane then dichloromethane/methanol(90/10 by volume)]. After concentration of the fractions under reducedpressure, 200 mg of3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazoleare obtained in the form of an amorphous white powder, along with 240 mgof a mixture consisting of3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazoleand of 3-benzyloxy-4-phenyl-1H-pyrazole. The mixture is again purifiedby chromatography on 10 g of silica gel [eluent:dichloromethane/methanol (50/50 then 90/10 by volume)] to give 90 mg of3-benzyloxy-4-phenyl-1H-pyrazole and 140 mg of3-benzyloxy-1-[2-(1-methylpyrrolidin-2-yl)-ethyl]-4-phenyl-1H-pyrazole,having the same appearance as the previous batch. LCMS (electrospray):m/z 362 (MH⁺).

The 1-methyl-2-(2-chloroethyl)pyrrolidine can be prepared in thefollowing way:

A solution of 330 mg of 1-methyl-2-(2-chloroethyl)pyrrolidinehydrochloride and of 5 cm³ of 1N sodium hydroxide in 20 cm³ ofdichloromethane is stirred at a temperature in the region of 20° C. for1 h. The reaction medium is extracted with dichloromethane. The organicphase is washed with a saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reduced pressure(2.7 kPa) to give 255 mg of 1-methyl-2-(2-chloroethyl)pyrrolidine, whichare immediately used in a reaction.

EXAMPLE 59 1-(Pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol dihydrochloride

A suspension of 608 mg of3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride and60 mg of palladium-on-charcoal at 10% in 18 cm³ of ethanol ishydrogenated at a temperature in the region of 20° C. under anatmosphere of 1300 mbar for 3 h. The reaction medium is diluted withmethanol, filtered over hyflosupercel and rinsed with methanol. Thefiltrate is evaporated under reduced pressure (2.7 kPa) to give 365 mgof a white powder. This reaction crude is recrystallized from 20 cm³ ofethanol at reflux. The solution obtained is allowed to return to atemperature in the region of 20° C., and is then immersed in an icebath. The crystals obtained are filtered under cold conditions throughan Iena filter, rinsed successively with ethanol and then ethyl etherand dried under vacuum (13 kPa) to give 185 mg of1-(pyrrolidin-3-yl)-4-phenyl-1H-pyrazol-3-ol dihydrochloride in the formof a white powder. LCMS (electrospray): m/z 230 (MH⁺).

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): 2.32 (m: 2H); 3.37 (m,in water: 2H); 3.45 (dd, J=12.5 and 5.0 Hz: 1H); 3.60 (dd, J=12.5 and7.0 Hz: 1H); 4.91 (m: 1H); 7.13 (t, J=7.5 Hz: 1H); 7.32 (t, J=7.5 Hz:2H), 7.66 (t, J=7.5 Hz: 2H); 8.11 (s: 1H); 9.44 (s: 2H); 10.40 (s: 1H).

The 3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloridecan be prepared in the following way:

6 cm³ of a 3M solution of hydrochloric acid in ethyl acetate are addeddropwise to a solution of 569 mg of3-benzyloxy-1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-4-phenyl-1H-pyrazolein 6 cm³ of ethyl acetate stirred at 0° C. The reaction medium isstirred at a temperature in the region of 20° C. for 2 h, before beingconcentrated under reduced pressure to give 608 mg of3-benzyloxy-4-phenyl-1-(pyrrolidin-3-yl)-1H-pyrazole dihydrochloride, inthe form of a white powder, which are used immediately.

The3-benzyloxy-1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-4-phenyl-1H-pyrazolecan be prepared in the following way:

129 mg of sodium hydride (at 50% in oil) are added to a solution of 450mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 9 cm³ of dimethylformamide,stirred under a nitrogen atmosphere at 0° C. After stirring at atemperature in the region of 20° C. for 30 min, 621 mg ofmethanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-3-yl) ester areadded. The reaction medium is stirred for 1 h at 80° C. and then pouredinto a water/ethyl acetate mixture. After stirring for 5 min, the mediumis separated by settling out and the aqueous phase is extracted threetimes with ethyl acetate. The organic phases are pooled, washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered through an Iena filter, rinsed with ethyl acetate andevaporated under reduced pressure (2.7 kPa) to give 998 mg of an oilwhich is purified by chromatography on a column of 70 g of silica(irregular 15-40 μm Merck) [eluent: dichloromethane/methanol (98/2 byvolume); flow rate: 15 cm³/min; detection: 250 nm]. After concentrationof the fractions under reduced pressure, 956 mg of a product areobtained, which is again purified by chromatography on a column of 90 gof silica (irregular 15-40 μm Merck) [eluent: dichloromethane/ethylacetate (98/2 by volume); flow rate: 15 cm³/min; detection: 250 nm].After concentration of the fractions under reduced pressure, 575 mg of3-benzyloxy-1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-4-phenyl-1H-pyrazoleare recovered in the form of a colorless foam. LCMS (electrospray): m/z420 (MH⁺), m/z 364 [MH⁺-tBu], m/z 320 [MH⁺−Boc].

The methanesulfonic acid (1-tert-butoxycarbonylpyrrolidin-3-yl) estercan be prepared in the following way:

A solution of 0.33 cm³ of methanesulfonyl chloride in 3.2 cm³ ofdichloromethane is added dropwise to a solution of 710 mg of1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 0.62 cm³ of triethylaminein 14.2 cm³ of dichloromethane, stirred under a nitrogen atmosphere at−10° C. The reaction medium is stirred at −10° C. for 5 min, and then ata temperature in the region of 20° C. for 2 h, before being concentratedto dryness under reduced pressure (2.7 kPa). The residue obtained istaken up with water and ethyl acetate. The solution is stirred for 5 minand is then separated by settling out. The aqueous phase is extractedthree times with ethyl acetate. The organic phases are pooled, washedsuccessively with an aqueous solution of sodium bicarbonate at 5% and ofsodium chloride, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure (2.7 kPa) to give 938 mg of methanesulfonic acid(1-tert-butoxycarbonylpyrrolidin-3-yl) ester in the form of a paleyellow oil. LCMS (electrospray): m/z 266 (MH⁺), m/z 210 [MH⁺-tBu].

The 1-tert-butoxycarbonyl-3-hydroxypyrrolidine can be prepared in thefollowing way:

A solution of 2.78 cm³ of triethylamine and 3.27 g of di-tert-butyldicarbonate is added to 0.848 cm³ of 3-hydroxypyrrolidine in a mixtureof 30 cm³ of tetrahydrofuran and 9.6 cm³ of water. The reaction mediumis stirred at a temperature in the region of 20° C. for 3 h, and is thenconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is taken up with water and ethyl acetate. The solution isstirred for 5 min, and is then separated by settling out. The aqueousphase is extracted three times with ethyl acetate. The organic phasesare pooled, dried over magnesium sulfate, filtered through an Ienafilter and then concentrated to dryness under reduced pressure (2.7 kPa)to give 1.823 g of 1-tert-butoxycarbonyl-3-hydroxypyrrolidine in theform of colorless crystals. m/z 188 (MH⁺), m/z 132 [MH⁺-tBu].

EXAMPLE 601-[(1-Methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazol-3-ol

3.75 cm³ of a 4M hydrochloric acid solution are added to a solution of263 mg of3-benzyloxy-1-[(1-methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazolein 2 cm³ of ethanol. The reaction medium is stirred at reflux for 7 hand is then concentrated under reduced pressure. The violet oil obtainedis taken up three times with 10 cm³ of isopropanol and then evaporatedto dryness under reduced pressure, to give 259 mg of violet resin. Thisresin is dissolved in a mixture of 0.6 cm³ of ethanol and 3 cm³ of1,4-dioxane. After the addition of 0.665 cm³ of a 4M solution ofhydrogen chloride in 1,4-dioxane and stirring at ambient temperature,the medium is concentrated under reduced pressure at 40° C. The residueis dissolved in 10 cm³ of water and the solution obtained is washed withdichloromethane (3×1 cm³) and then brought to pH 9-10 by adding sodiumcarbonate. After extraction with dichloromethane, the organic phases arepooled and then dried over magnesium sulfate, filtered and concentratedunder reduced pressure at 35° C. The pale pink solid obtained (124 mg)is recrystallized under hot conditions from ethanol, so as to give 73 mgof 1-[(1-methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazol-3-ol inthe form of a white solid. LCMS (electrospray): m/z 258 (MH⁺).

¹H NMR spectrum (400 MHz, DMSO d6, δ in ppm): 1.63 (m: 1H); 1.76 (m:2H); 1.95 (m: 1H); 2.30 (partially masked m: 1H); 2.34 (s: 3H); 2.82 (m:1H); 3.14 (m: 1H); 3.90 (dd, J=7-14 Hz: 1H); 4.11 (dd, J=6-14 Hz: 1H);7.18 (bt, J=8 Hz: 1H); 7.35 (bt, J=8 Hz: 2H); 7.57 (s: 1H); 7.70 (bd,J=8 Hz: 2H).

The3-benzyloxy-1-[(1-methylpyrrolidin-2-(S)-yl)-methyl]-4-phenyl-1H-pyrazolecan be prepared in the following way:

136 mg of sodium hydride (at 50% in oil) are added to a solution of 283mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 6 cm³ of dimethylformamide,stirred under a nitrogen atmosphere at ambient temperature. Afterstirring at ambient temperature for 30 min, a solution of 250 mg of1-methyl-2-(S)-chloromethylpyrrolidine hydrochloride in 6 cm³ ofdimethylformamide is added. The reaction medium is stirred at 80° C. for1 h, and is then cooled to ambient temperature and hydrolyzed. Afterextraction with ethyl acetate, the organic phases are pooled, washedwith a saturated aqueous sodium bicarbonate solution, dried overmagnesium sulfate, filtered and concentrated under reduced pressure at35° C. to give 554 mg of a yellow oil. After purification bychromatography under a column of 30 g of silica (irregular 15-40 μmMerck) [eluent: dichloromethane/-methanol (98/2); flow rate: 15 cm³/min]and concentration of the fractions under reduced pressure, 263 mg of3-benzyloxy-1-[(1-methylpyrrolidin-2-(S)-yl)methyl]-4-phenyl-1H-pyrazoleare obtained. LCMS (electrospray): m/z 348 (MH⁺).

The 1-methyl-2-(S)-chloromethylpyrrolidine hydrochloride can be preparedin the following way:

388 μl of thionyl chloride are added slowly to a solution of 250 mg of(S)-(−)-1-methyl-2-pyrrolidine methanol in 2 cm³ of dichloromethanecooled in a bath of ice-cold water. The solution obtained is heated atreflux for 3 hours and then stirred at ambient temperature for 18 hours.After evaporation under reduced pressure at 35° C., the brown residueobtained is dissolved in ethanol and then concentrated to dryness underreduced pressure. The dry extract obtained is dissolved in 1 cm³ ofethanol and then precipitated by gradually adding 6 cm³ of ethyl ether.The suspension obtained is cooled using a bath of ice-cold water and thesolid is filtered off and then washed with ethyl ether. After dryingunder vacuum, 258 mg of 1-methyl-2-(S)chloromethylpyrrolidinehydrochloride are obtained in the form of a very hygroscopic ochresolid. Mass spectrum (EI): m/z 133 (M^(+.)).

EXAMPLE 61 4-Phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-olhydrochloride

163.5 mg of 1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-olhydrochloride in 5 cm³ of methanol, 139.4 mg of ammonium formate and 10mg of palladium-on-charcoal at 10% are added to a reactor for amicrowave oven equipped with a magnetic stirrer. The tube is sealed andplaced in a microwave device for 60 seconds at a temperature of 100° C.under a pressure of 10.5 bar. The reaction medium is filtered throughAcodisc GHP Polypro (PALL) and then rinsed with methanol. The filtrateis concentrated to dryness under reduced pressure, to give a gum whichis solidified with ethanol. 40 mg of a white powder are thus obtained.The operation is repeated with the above ethanolic filtrate to give,after combining the two batches, 52 mg of a white powder. The finalethanolic filtrate is again concentrated to dryness, and the residueobtained is taken up with 10 cm³ of water. The solution is chilled andthen lyophilized overnight. The various batches are combined, to give 80mg of 4-phenyl-1-pyrrolidin-3-ylmethyl-1H-pyrazol-3-ol hydrochloride inthe form of a white powder. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ inppm): 1.66 (m, 1H); 1.99 (m, 1H); 2.73 (m, 1H); 2.92 (m, 1H); from 3.02to 3.25 (m, 2H); 4.01 (d, J=7.0 Hz, 2H); 7.12 (broad t, J=7.5 Hz, 1H);7.32 (broad t, J=7.5 Hz, 2H); 7.65 (broad d, J=7.5 Hz, 2H); 7.99 (s,1H); 8.36 (broad s, 1H); from 6.70 to 8.70 (very very broad m, 1H). Massspectrum (EI): m/z 244⁺ (M+H)⁺.

The 1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-olhydrochloride can be prepared in the following way:

A suspension of 937 mg of3-benzyloxy-1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazolehydrochloride and 93 mg of palladium-on-charcoal at 10% in 9.4 cm³ ofethanol is hydrogenated at a temperature in the region of 20° C. underan atmosphere of 1500 mbar for 16 h. The reaction medium is filteredthrough hyflosupercel and rinsed with ethanol. After concentration ofthe filtrate to dryness, 350 mg of a beige gum are obtained, which gumis recrystallized from ethanol. After filtration through an iena funnel,rinsing with ethyl ether and then drying in an industrial vacuum oven,178 mg of 1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrrazol-3-olhydrochloride are obtained. Mass spectrum (EI): m/z 334⁺[(M+H)⁺—HCl].

The 3-benzyloxy-1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazolehydrochloride can be prepared in the following way:

129 mg of sodium hydride (at 50% in oil) are added, in a single step, toa solution of 450 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 9 cm³ ofanhydrous dimethylformamide stirred under an argon atmosphere at 0° C.After stirring for 30 min at a temperature in the region of 20° C., asolution of 630 mg of methanesulfonic acid(1-benzylpyrrolidin-3-ylmethyl) ester in 9 cm³ of anhydrousdimethylformamide is added. The reaction medium is stirred for 4 h at80° C. and then plunged into a water/ethyl acetate mixture. Afterstirring for 5 min, the medium is separated by settling out and theaqueous phase is extracted three times with ethyl acetate. The organicphases are combined, washed twice with water and then once with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and filtered through an iena funnel. The magnesium sulfate isrinsed with ethyl acetate. The combined organic phases are evaporatedunder reduced pressure and the residue obtained is dried overnight on avane pump, to give 939 mg of a pale yellow oil which is purified bychromatography on a column of 90 g of silica (Merck irregular silica15-40 μm) [eluent: dichloromethane/methanol (98/2 by volume); flow rate:10 cm³/min; detection: 250 nm]. After concentration of the fractionsunder reduced pressure, 586 mg of 83%-pure3-benzyloxy-1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazole areobtained in the form of a foam. This is taken up with water (pH=1) andthen ethyl acetate is added thereto. After stirring for 5 min, themedium is separated by settling out and the aqueous phase is extractedwith ethyl acetate. The organic phases are brought to pH=9 with anammonium hydroxide solution, extracted three times with ethyl acetate,combined, dried over magnesium sulfate, filtered, rinsed, and thenconcentrated to dryness under reduced pressure, to give 497 mg of3-benzyloxy-1-(1-benzylpyrrolidin-3-ylmethyl)-4-phenyl-1H-pyrazole inthe form of a free base. The product is taken up with 5 cm³ of ethylacetate. The medium is cooled to 0° C., before the addition of 5 cm³ ofa 3M hydrochloric acid solution in ethyl acetate. The solution isconcentrated to dryness under reduced pressure, to give a brown oil.Attempts to crystallize the crude residue obtained were carried out invain (ethyl acetate, ethanol, methanol, diethyl ether or hexane). 940 mgof 3-benzyloxy-1-(1-benzylpyrrolidin-3-ylmethyl]-4-phenyl-1H-pyrazolehydrochloride are thus recovered. Mass spectrum (EI): m/z 424⁺ (M+H)⁺.

The methanesulfonic acid (1-benzylpyrrolidin-3-ylmethyl) ester can beprepared in the following way:

A solution of 0.455 cm³ of methanesulfonic chloride in 9.7 cm³ ofanhydrous dichloromethane is added dropwise to a solution of 1 g of(1-benzylpyrrolidin-3-yl)methanol and 0.844 cm³ of triethylamine in 20cm³ of dichloromethane, stirred under an argon atmosphere at 0° C. Thereaction medium is stirred for 5 min at 0° C. and then for 2 h at atemperature close to 20° C., before being concentrated to dryness underreduced pressure. The residue obtained is taken up with water and ethylacetate. The solution is stirred for 5 min and is then separated bysettling out. The aqueous phase is extracted three times with ethylacetate. The organic phases are combined, washed successively with anaqueous 5% sodium bicarbonate solution and with a saturated aqueoussodium chloride solution, dried over magnesium sulfate, filtered, andevaporated under reduced pressure, to give 1.2 g of methanesulfonic acid(1-benzylpyrrolidin-3-ylmethyl) ester. Mass spectrum (EI): m/z 270⁺(M+H)⁺.

The (1-benzylpyrrolidin-3-yl)methanol can be prepared in the followingway:

17.1 cm³ of a 1M lithium aluminum hydride solution in tetrahydrofuranare added to a solution of 2 g of 1-benzyl-5-oxopyrrolidine-3-carboxylicacid methyl ester in 40 cm³ of tetrahydrofuran, stirred at 0° C. under anitrogen atmosphere. After stirring for 15 min at 0° C., the reactionmedium is allowed to return to a temperature in the region of 20° C. andis stirred for 4 h. A mixture consisting of 0.65 cm³ of water and of 6.5cm³ of tetrahydrofuran is added dropwise to the reaction medium. 0.65cm³ of a 15% aqueous sodium hydroxide solution and 1.95 cm³ of water arethen successively added. The medium is stirred at a temperature in theregion of 20° C. until the formation of a filterable solid, to which twospatulas of magnesium sulfate are added. After filtration through aniena funnel, rinsing and concentrating to dryness under reducedpressure, 1.72 g of (1-benzylpyrrolidin-3-yl)methanol are obtained inthe form of a colorless oil. Mass spectrum (EI): m/z 192⁺ (M+H)⁺.

EXAMPLE 621-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol

2.89 cm³ of 6N hydrochloric acid are added to a solution of 211 mg of3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazolein 1.5 cm³ of ethanol. The reaction medium is stirred for 5 h 30 min at110° C. before being concentrated to dryness under reduced pressure. Theresidue is taken up with isopropanol and is concentrated to dryness, togive 136 mg of a foam which is crystallized from a minimum amount ofethanol under hot conditions. After chilling overnight, nocrystallization is apparent. The residue is taken up with 5 cm³ of waterand extracted three times with 1 cm³ of dichloromethane, brought to pH9-10 with solid sodium carbonate. The aqueous phase is again extractedthree times with dichloromethane. The organic phases are combined, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure, to give 100 mg of a product which is recrystallizedfrom a minimum amount of ethanol. After leaving the product overnight ina refrigerator, filtering and drying, 58 mg of1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol areobtained in the form of a white solid. ¹H NMR spectrum (400 MHz,(CD₃)₂SO d6 with a drop of AcOH d4, δ in ppm): from 1.62 to 2.00 (m,4H); 2.42 (s, 3H); 3.02 (m, 1H); 3.21 (m, 2H); 3.96 (dd, J=7.0 and 14.0Hz, 1H); 4.13 (dd, J=5.5 and 14.0 Hz, 1H); 7.13 (broad t, J=7.5 Hz, 1H);7.33 (broad t, J=7.5 Hz, 2H); 7.65 (broad d, J=7.5 Hz, 2H); 7.97 (s,1H). Mass spectrum (EI): 258(+)=(M+H)(+). The3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazolecan be prepared in the following way:

A solution of 400 mg of3-benzyloxy-4-phenyl-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolehydrochloride, 297 mg of potassium carbonate and 0.101 cm³ of methyliodide in 4 cm³ of dimethylformamide is stirred overnight at atemperature in the region of 20° C. The medium is diluted with water andthen extracted with ethyl acetate. The organic phase is dried overmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure, to give a reaction crude which is purified by chromatographyon silica gel (eluent: dichloromethane containing 3% of methanol).

After concentration of the fractions to dryness, 215 mg of3-benzyloxy-1-((2R)-1-methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazoleare obtained.

The 3-benzyloxy-4-phenyl-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolehydrochloride can be prepared in the following way:

3.17 cm³ of a 4N hydrochloric acid solution in dioxane are added to asolution of 500 mg of3-benzyloxy-1-((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazolein 5 cm³ of dioxane. The reaction medium is stirred overnight at atemperature in the region of 20° C. and is then concentrated to drynessunder reduced pressure, to give 400 mg of3-benzyloxy-4-phenyl-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolehydrochloride in the form of a white solid. Mass spectrum (EI): m/z 334⁺(M+H)⁺, m/z 667⁺ (2M+H)⁺.

The3-benzyloxy-4-phenyl-1-((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl)-1H-pyrazolecan be prepared in the following way:

A solution of 251 mg of 3-benzyloxy-4-phenyl-1H-pyrazole and 72 mg ofsodium hydride (50% in oil) in 5 cm³ of dimethylformamide is stirred for1 h before adding a solution of 364 mg of methanesulfonic acid((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl) ester in 5 cm³ ofdimethylformamide. The reaction medium is stirred at 80° C. for 3 h andis then poured into water. After extraction with ethyl acetate, theorganic phase is washed three times with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, and thenconcentrated to dryness, to give 440 mg of a crude product which ispurified by chromatography on silica gel (eluent: 80/20 heptane/ethylacetate). After concentration of the fractions to dryness, 202 mg of3-benzyloxy-4-phenyl-1-((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl)-1H-pyrazoleare obtained. Mass spectrum (EI): m/z 456⁺ (M+Na)⁺, m/z 434⁺ (M+H)⁺, m/z334⁺ [(M+H)⁺-CO₂tBu+H].

The methanesulfonic acid((2R)-1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl) ester can be preparedin the following way:

A solution of 1.2 cm³ of methanesulfonyl chloride in 20 cm³ ofdichloromethane is added dropwise to a solution of 3 g of(2R)-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine and 2.27 cm³ oftriethylamine in 65 cm³ of dichloromethane, stirred under a nitrogenatmosphere at −10° C. The reaction medium is allowed to return to 20°C., before concentrating to dryness under reduced pressure. The residueobtained is taken up with water, and extracted twice with 20 cm³ ofethyl acetate. The combined organic phases are washed three times with20 cm³ of a 5% aqueous sodium bicarbonate solution, dried over magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure,to give 3.75 g of a mixture of methanesulfonic acid((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl) ester and of(2R)-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine. The mixture isagain reacted under the same conditions as above, but with 0.3 eq oftriethylamine and 0.3 eq of methanesulfonyl chloride. After a similartreatment, 3.63 g of methanesulfonic acid((2R)-1-tert-butoxycarbonylpyrrolidin-2-ylmethyl) ester are obtained inthe form of a colorless liquid. Mass spectrum (EI): m/z 280⁺ (M+H)⁺.

EXAMPLE 63 4-Phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol hydrochloride

A suspension of 130 mg of3-benzyloxy-4-phenyl-1-(piperidin-3-yl)-1H-pyrazole hydrochloride and 13mg of palladium-on-charcoal at 10% in 4 cm³ of ethanol is hydrogenatedat a temperature in the region of 20° C. under an atmosphere of 1500mbar for 3 h. The reaction medium is taken up with a mixture of 15 cm³of 80/20 by volume dichloromethane/methanol, spin-filtered throughClarcel, and then washed twice with 10 cm³ of an 80/20 by volumedichloromethane/methanol mixture. After concentration to dryness, thecrystalline product is taken up with 5 cm³ of ethyl acetate,spin-filtered, and taken up twice with 0.5 cm³ of ethyl acetate, to give70 mg of 4-phenyl-1-(piperidin-3-yl)-1H-pyrazol-3-ol hydrochloride inthe form of a crystalline product.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.72 to 2.22 (m,4H); 2.86 (m, 1H); from 3.10 to 3.57 (partially masked m, 3H); 4.36 (m,1H); 7.14 (broad t, J=7.5 Hz, 1H); 7.33 (broad t, J=7.5 Hz, 2H); 7.68(broad d, J=7.5H, 2H); 8.07 (s, 1H); 9.18 (broad m, 2H); 10.4 (broad s,1H). Mass spectrum (EI): m/z 244+(M+H)⁺.

The 3-benzyloxy-4-phenyl-1-(piperidin-3-yl)-1H-pyrazole hydrochloridecan be prepared in the following way:

2 cm³ of a 4N hydrochloric acid solution in ethyl acetate are added to asolution of 230 mg of3-benzyloxy-1-(1-tert-butoxycarbonylpiperidin-3-yl)-4-phenyl-1H-pyrazolein 2 cm³ of ethyl acetate, cooled by means of an ice bath. The reactionmedium is allowed to return to a temperature in the region of 20° C. andis then stirred for 2 h 30 min before concentration of the ethylacetate. The residue is taken up three times with 2 cm³ of diethyl etherand the insoluble material is filtered off, to give 150 mg of3-benzyloxy-4-phenyl-1-(piperidin-3-yl)-1H-pyrazole hydrochloride. Massspectrum (EI): m/z 334⁺ (M+H)⁺, m/z 36⁺/38⁺ HCl⁺.

The3-benzyloxy-1-(1-tert-butoxycarbonylpiperidin-3-yl)-4-phenyl-1H-pyrazolecan be prepared in the following way:

153 mg of sodium hydride (at 50% in oil) are added, in three portions,to a solution of 725 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in 7 cm³ ofanhydrous dimethylformamide, stirred under a nitrogen atmosphere. Afterstirring for 45 min at a temperature in the region of 20° C., a solutionof 890 mg of methanesulfonic acid (1-tert-butoxycarbonylpiperidin-3-yl)ester in 4.5 cm³ of anhydrous dimethylformamide is added. The reactionmedium is stirred for 3 h at 80° C. and is then, after cooling, pouredinto water. The aqueous phase is extracted four times with 50 cm³ ofethyl acetate. The combined organic phases are washed with a saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and then concentrated to dryness under reduced pressure. Theproduct obtained is taken up with dichloromethane, which, afterspin-filtering, gives 380 mg of 3-benzyloxy-4-phenyl-1H-pyrazole in theform of a beige solid. The filtrate, after concentration to dryness, ispurified by chromatography on a column of 70 g of silica (Merck, eluent:95/5 by volume dichloromethane/ethyl acetate). After concentration ofthe fractions under reduced pressure, 280 mg of3-benzyloxy-1-(1-tert-butoxycarbonylpiperidin-3-yl)-4-phenyl-1H-pyrazoleare obtained with a purity of 70%. These 280 mg are again purified bychromatography on a column of 30 g of silica (Merck, eluent: 70/30 byvolume dichloromethane/heptane). After concentration of the fractionsunder reduced pressure, 230 mg of3-benzyloxy-1-(1-tert-butoxycarbonylpiperidin-3-yl)-4-phenyl-1H-pyrazoleare obtained.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.20 (m, 1H); 1.41 (s,9H); from 1.45 to 2.16 (m, 3H); 2.93 (m, 1H); from 3.00 to 3.40 (broadm, 1H); 3.79 (m, 1H); from 3.98 to 4.16 (m, 2H); 5.31 (broad s, 2H);7.15 (broad t, J=7.5 Hz, 1H); from 7.30 to 7.45 (m, 5H); 7.51 (broad d,J=7.5 Hz, 2H); 7.65 (broad d, J=7.5 Hz, 2H); 8.14 (s, 1H).

The methanesulfonic acid (1-tert-butoxycarbonylpiperidin-3-yl) ester canbe prepared in the following way:

A solution of 0.305 cm³ of methanesulfonyl chloride is added dropwise toa solution of 750 mg of 1-tert-butoxycarbonyl-3-hydroxypiperidine and0.570 cm³ of triethylamine in 7 cm³ of dichloromethane, stirred under anitrogen atmosphere at −10° C. The reaction medium is allowed to returnto a temperature in the region of 20° C. and is stirred for 3 h, beforeconcentrating to dryness under reduced pressure. The residue obtained istaken up with ethyl acetate. The organic phase is successively washedwith a 5% aqueous sodium bicarbonate solution and then a saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated to dryness under reduced pressure, to give0.9 g of methanesulfonic acid (1-tert-butoxycarbonylpiperidin-3-yl)ester in the form of a colorless oil. Mass spectrum (EI): m/z 280⁺(M+H)⁺, m/z 224⁺ [(M+H)⁺-tBu+H].

EXAMPLE 64 1-(1-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-olhydrochloride

A solution of 610 mg of3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole in 12cm³ of ethyl acetate and 6 cm³ of a 4M hydrochloric solution in ethylacetate is stirred for 15 min at a temperature in the region of 20° C.After concentration to dryness under reduced pressure, 669 mg of3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazolehydrochloride are obtained, which product is immediately reacted again.A suspension of 669 mg of the preceding hydrochloride and 66 mg ofpalladium-on-charcoal at 10% in 15 cm³ of ethanol is hydrogenated at atemperature in the region of 20° C. under an atmosphere of 1500 mbar for3 h. The reaction medium is taken up with a mixture of 25 cm³ of 80/20dichloromethane/methanol and then spin-filtered through Clarcel. Afterconcentration to dryness, the product obtained is dissolved in 20 cm³ ofwater and then lyophilized, to give 500 mg of1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol hydrochloride.¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 at 353K, δ in ppm): from 1.37 to1.87 (m, 6H); 2.86 (broad m, 4H); from 3.32 to 3.60 (very broad m, 2H);4.24 (broad m, 1H); 4.50 (broad m, 1H); 7.16 (broad t, J=7.5 Hz, 1H);7.34 (broad t, J=7.5 Hz, 2H); 7.67 (broad d, J=7.5 Hz, 2H); 7.97 (s,1H); from 10.0 to 10.6 (very broad m, 2H). Mass spectrum (EI): m/z 272⁺(M+H)⁺, m/z 36⁺/38⁺ HCl⁺.

EXAMPLE 65 1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride

The 1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol hydrochloride canbe prepared according to the same method used for preparing the1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol hydrochloride,but using 470 mg of3-benzyloxy-1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazole, 10 cm³ ofethyl acetate, 5 cm³ of a 4M hydrochloric acid solution in ethylacetate, and then 51 mg of palladium-on-charcoal at 10% and 15 cm³ ofethanol. According to the same treatment conditions, 400 mg of1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazol-3-ol hydrochloride are thusobtained. ¹H NMR spectrum (400 MHz, (CD₃)₂SO d6 at 343K, δ in ppm): from1.62 to 2.32 (m, 6H); 2.86 (broad s, 3H); from 2.92 to 3.76 (partiallymasked m, 4H); from 4.62 to 4.92 (very broad m, 1H); 7.15 (broad t,J=7.5 Hz, 1H); 7.33 (broad t, J=7.5 Hz, 2H); 7.65 (broad d, J=7.5 Hz,2H); 7.93 (broad s, 1H); from 9.85 to 10.3 (broad m, 1H); from 10.7 to11.4 (very broad m, 1H). Mass spectrum (EI): m/z 272⁺ (M+H)⁺.

The 3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazoleand 3-benzyloxy-1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazole can beprepared in the following way:

426 mg of sodium hydride (at 50% in oil) are added, in three portions,to a solution of 2 g of 3-benzyloxy-4-phenyl-1H-pyrazole in 20 cm³ ofanhydrous dimethylformamide, stirred under a nitrogen atmosphere. Afterstirring for 30 min at a temperature in the region of 20° C., 1.3 g of a75/25 mixture of 1-methyl-2-chloromethylpiperidine and ofmethanesulfonic acid (1-methylpiperidin-2-ylmethyl) ester are addeddropwise. The reaction medium is stirred for 3 h at 80° C. and then,after cooling, is poured into a water/ice mixture. The aqueous phase isextracted with ethyl acetate. The organic phase is washed with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and then concentrated to dryness under reducedpressure. The product is purified by two successive chromatographies ona column of 119 g of silica (Merck, eluent: 97/3 by volumedichloromethane/methanol). After concentration of the fractions underreduced pressure, 460 mg of3-benzyloxy-1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazole and 650 mg of3-benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole areobtained.

3-Benzyloxy-1-(1-methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazole. ¹HNMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): from 1.12 to 1.65 (m,6H); 2.06 (m, 1H); 2.29 (s, 3H); 2.34 (m, 1H); 2.77 (m, 1H); 3.86 (dd,J=7.5 and 14.0 Hz, 1H); 4.25 (dd, J 5.5 and 14.0 Hz, 1H); 5.30 (s, 2H);7.14 (broad t, J=7.5 Hz, 1H); from 7.30 to 7.44 (m, 5H); 7.50 (broad d,J=7.5 Hz, 2H); 7.64 (broad d, J=7.5 Hz, 2H); 8.06 (s, 1H).3-Benzyloxy-1-(1-methylazepan-3-yl)-4-phenyl-1H-pyrazole. ¹H NMRspectrum (400 MHz, (CD₃)₂SO d6, δ in ppm): from 1.56 to 1.82 (m, 4H);from 1.96 to 2.08 (m, 2H); 2.33 (s, 3H); from 2.50 to 2.93 (partiallymasked m, 4H); 4.26 (m, 1H); 5.30 (s, 2H); 7.13 (broad t, J=7.5 Hz, 1H);from 7.28 to 7.45 (m, 5H); 7.51 (broad d, J=7.5 Hz, 2H); 7.65 (broad d,J=7.5 Hz, 2H); 8.11 (s, 1H).

The mixture of 2-chloromethyl-1-methylpiperidin and of methanesulfonicacid (1-methylpiperidin-2-ylmethyl) ester can be prepared in thefollowing way:

A solution of 0.815 cm³ of methanesulfonyl chloride is added dropwise toa solution of 1.31 cm³ of (1-methylpiperidin-2-yl)methanol and 1.53 cm³of triethylamine in 26 cm³ of dichloromethane, stirred under a nitrogenatmosphere at −10° C. The reaction medium is allowed to return to atemperature in the region of 20° C. and is stirred for 3 h beforeconcentration to dryness under reduced pressure. The residue obtained istaken up with ethyl acetate. The organic phase is successively washedwith a 5% aqueous sodium bicarbonate solution and then a saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated to dryness under reduced pressure, to give1.3 g of a 75/25 mixture of 2-chloromethyl-1-methylpiperidin and ofmethanesulfonic acid (1-methylpiperidin-2-ylmethyl) ester. Mass spectrum(EI): m/z 148⁺ (M+H)⁺, m/z 208⁺ (M+H)⁺.

EXAMPLE 66 4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The procedure is carried out as in example 38, but with 0.75 g of3-benzyloxy-4-phenyl-1(2-piperidin-1-ylethyl)-1H-pyrazol oxalate, 5.9cm³ of 12N hydrochloric acid and 5.9 cm³ of ethanol. The mixture isheated for 4 hours at a temperature close to 100° C. After cooling to atemperature close to 20° C., the reaction medium is taken up withethanol, and concentrated to dryness under reduced pressure (2 kPa); theresidue is precipitated from a mixture of diisopropyl ether and ethanol.0.357 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride is obtained in the form of a white solid. ¹H NMR spectrum(300 MHz)-δ in ppm in DMSO-d6: 1,40 (m, 1H); from 1.63 to 1.87 (m, 5H);2.92 (m, 2H); from 3.36 to 3.52 (m, 4H); 4.43 (t, J=6.5 Hz, 2H); 7.14(tt, J=1.5 and 7.5 Hz, 1H); 7.33 (broad t, J=7.5 Hz, 2H); 7.64 (broad d,J=7.5 Hz, 2H); 8.05 (s, 1H); from 10.35 to 10.72 (broad m, 2H).

IR spectrum (KBr): 2939; 1606; 1581; 1520; 1454; 1444; 1170; 771; 700;673 and 427 cm⁻¹.

The 3-benzyloxy-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalatecan be obtained in the following way:

The procedure is carried out as in example 15, but with 0.166 g ofsodium hydride (at 75% by mass in liquid petroleum jelly), 0.515 g of1-(2-chloroethyl)-piperidine hydrochloride and 0.5 g of3-benzyloxy-4-phenylpyrazole. 0.754 g of3-benzyloxy-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate isthus obtained in the form of a white powder. IR spectrum (KBr): 2930;2638; 2542; 1606; 1511; 1454; 1357; 1280; 1181; 763; 721; 697 and 501cm⁻¹. Mass spectrum (CI): m/z=362 (MH)⁺ base peak.

4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate

The procedure is carried out as in example 15, but with 0.231 g ofsodium hydride (at 75% by mass in liquid petroleum jelly), 0.715 g of1-(2-chloroethyl)piperidine hydrochloride and 0.4 g of 4-phenylpyrazole.0.832 g of 4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate arethus obtained in the form of white crystals.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.60 (m, 2H); 1.79 (m,4H); 3.06 (m, 4H); 3.43 (t, J=6.5 Hz, 2H); 4.58 (t, J=6.5 Hz, 2H); 7.32(broad t, J=7.5 Hz, 1H); 7.48 (broad t, J=7.5 Hz, 2H); 7.69 (broad d,J=7.5 Hz, 2H); 8.06 (s, 1H); 8.33 (s, 1H).

IR spectrum (KBr): 2949; 1679; 1713; 1606; 1460; 1187; 955; 763; 703 and476 cm⁻¹.

EXAMPLE 67 4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

A suspension of 0.15 g of4-(5-chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride and 5 mg of palladium-on-charcoal (at 10%) in 15 cm³ ofmethanol is stirred in an autoclave under a hydrogen pressure of 3000kPa, at a temperature of 60° C. for 20 hours. The reaction medium isthen filtered through Celite®, rinsed with methanol and concentrated todryness under reduced pressure (3 kPa). The residue is triturated withdiisopropyl ether; after filtration of the solid which has appeared anddrying under vacuum (70 Pa) at a temperature of 60° C., 0.1 g of4-(thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride is obtained in the form of a gray powder which melts ataround 180° C. (with decomposition). ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: 1.40 (m, 1H); from 1.62 to 1.85 (m, 5H); from 2.82 to3.02 (broad m, 2H); from 3.30 to 3.52 (partially masked m, 4H); 4.40(broad t, J=6.5 Hz, 2H); 7.02 (m, 1H); 7.19 (m, 1H); 7.32 (m, 1H); 7.93(broad s, 1H); from 10.1 to 10.65 (broad m, 2H). IR spectrum, KBr: 2952;2539; 1605; 1545; 1455; 1404; 1175; 969 and 697 cm⁻¹.

EXAMPLE 684-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The procedure is carried out as in example 38 but with 0.47 g of3-benzyloxy-4-(3,4-dichlorophenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazole,3 cm³ of 12N hydrochloric acid and 10 cm³ of ethanol. The mixture isheated for 24 hours at a temperature close to 100° C. After cooling to atemperature close to 20° C., the reaction medium is taken up with threetimes 30 cm³ of toluene and then three times 30 cm³ of acetone theethanol, concentrated to dryness under reduced pressure (2 kPa); theresidue is precipitated from 30 cm³ of acetone. 0.26 g of4-(3,4-dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride is obtained in the form of a whitish powder. ¹H NMRspectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.32 to 1.92 (m, 6H); from2.85 to 3.60 (m, 6H); 4.36 (broad m, 2H); from 7.55 to 7.68 (m, 2H);7.90 (d, J=2.0 Hz, 1H); 8.15 (broad s, 1H); from 9.35 to 9.48 (broad m,1H); 10.8 (broad s, 1H). IR spectrum, KBr: 2945; 2533; 1604; 1525; 1448;1180; 1028 and 806 cm⁻¹.

3-Benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole

The procedure is carried out as in example 15, but with 0.135 g ofsodium hydride (75% by mass in liquid petroleum jelly), 0.519 g of1-(2-chloroethyl)-piperidine hydrochloride and 0.45 g of3-benzyloxy-4-(3,4-dichlorophenyl)pyrazole. After heating the reactionmedium for 1 hour at 50° C. and then for 16 hours at 20° C., the mediumis taken up with 150 cm³ of ethyl acetate and 150 cm³ of water; theorganic phase is separated by settling out, washed with twice 100 cm³ ofdistilled water and 100 cm³ of a saturated aqueous sodium chloridesolution, dried over sodium sulfate, filtered, and concentrated todryness under reduced pressure (3 kPa). 0.6 g of3-benzyloxy-4-(3,4-dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleis thus obtained in the form of an orange-yellow oil. ¹H NMR spectrum(400 MHz)-δ in ppm-in DMSO-d6: 1.38 (m, 2H); 1.48 (m, 4H); 2.38 (m, 4H);2.68 (t, J=6.5 Hz, 2H); 4.07 (t, J=6.5 Hz, 2H); 5.33 (s, 2H); 7.36 (tt,J=1.5 and 7.5 Hz, 1H); 7.41 (broad t, J=7.5 Hz, 2H); 7.51 (d, J=7.5 Hz,2H); from 7.57 to 7.65 (m, 2H); 7.88 (d, J=2.5 Hz, 1H); 8.21 (m, 1H).Mass spectrum (CI): m/z=430 (MH⁺) base peak.

3-Benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 0.3 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazoleand 1.6 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran and 15 cm³ of tetrahydrofuran. 0.2 g of3-benzyloxy-4-(3,4-dichlorophenyl)-1H-pyrazole is thus obtained in theform of an oil which crystallizes. ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: 5.35 (s, 2H); from 7.32 to 7.46 (m, 3H); 7.50 (broad d, J=7.5Hz, 2H); 7.59 (d, J=9.0 Hz, 1H); 7.70 (dd, J=2.5 and 9.0 Hz, 1H); 7.95(d, J=2.5 Hz, 1H); 8.23 (s, 1H); 12.3 (broad m, 1H). Mass spectrum (EI):m/z=318 (M^(+.)), m/z=91 (C₇H₇ ⁺) base peak.

3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichlorophenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 0.3 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-pyrazole, 2.29 g of3,4-dichlorophenylboronic acid, 2.547 g of tripotassium phosphate, and0.421 g of dichlorobis(triphenylphosphine)palladium in 40 cm³ ofdimethoxyethane. After purification by chromatography, under a nitrogenpressure of 50 kPa, on a column of silica gel (particle size 20-45μ;diameter 4 cm; height 60 cm), eluting with a mixture of ethyl acetateand of cyclohexane (5/95 then 10/90 by volume), fractions 9 to 12 arecombined, and concentrated to dryness under reduced pressure (3 kPa).0.3 g of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(3,4-dichlorophenyl)-1H-pyrazole isthus obtained in the form of a white powder. Mass spectrum (EI): m/z=472(M^(+.)), m/z=317 [(M-C₇H₇SO₂)⁺], m/z=91 (C₇H₇ ⁺) base peak.

EXAMPLE 69 4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol

The procedure is carried out as in example 38, but with 0.32 g of3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 3cm³ of 12N hydrochloric acid and 10 cm³ of ethanol. The mixture isheated for 20 minutes at a temperature close to 100° C. After cooling toa temperature close to 20° C., the reaction medium is taken up with 5times 30 cm³ of acetone. After concentration to dryness under reducedpressure (3 kPa), the residue is triturated with 30 cm³ of diisopropylether and then purified by chromatography, under a nitrogen pressure of50 kPa, on a column of silica gel (particle size: 20-45μ; diameter 2 cm;height 20 cm), eluting with ethyl acetate then a mixture of ethylacetate and methanol (95/5 then 90/10 then 80/20 by volume). Fractions10 to 28 are combined, and concentrated to dryness under reducedpressure (3 kPa). 0.11 mg of4-(4-bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol is thusobtained in the form of a white powder. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.32 to 1.55 (m, 6H); 2.39 (m, 4H); 2.65 (t, J=6.5Hz, 2H); 4.00 (t, J=6.5 Hz, 2H); 7.50 (broad d, J=8.5 Hz, 2H); 7.62(broad d, J=8.5 Hz, 2H); 7.96 (s, 1H); from 10.3 to 10.50 (broad m, 1H).IR spectrum, KBr: 2941; 1631; 1601; 1529; 1173; 1007; 824 and 510 cm⁻¹.

3-Benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole

The procedure is carried out as in example 15, but with 2.77 g of sodiumhydride (at 75% by mass in liquid petroleum jelly), 1.063 g of1-(2-chloroethyl)piperidine hydrochloride and 0.95 g of3-benzyloxy-4-(4-bromophenyl)pyrazole. After heating the reaction mediumfor 1 hour at 50° C., the medium is cooled to a temperature close to 20°C., and taken up with 300 cm³ of ethyl acetate and 300 cm³ of water; theorganic phase is separated by settling out, dried over magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure (3kPa). The residue is purified by chromatography, under a nitrogenpressure of 50 kPa, on a column of silica gel (particle size 20-45μ;diameter 3 cm; height 40 cm), eluting with a mixture of ethyl acetateand of cyclohexane (5/95 then 10/95 by volume). Fractions 19 to 35 arecombined, and concentrated to dryness under reduced pressure (3 kPa).0.32 g of3-benzyloxy-4-(4-bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole isthus obtained in the form of a colorless oil. ¹H NMR spectrum (300MHz)-δ in ppm-in DMSO-d6:

From 1.34 to 1.53 (m, 6H); 2.38 (m, 4H); 2.68 (t, J=6.5 Hz, 2H); 4.07(t, J=6.5 Hz, 2H); 5.32 (s, 2H); from 7.32 to 7.55 (m, 7H); 7.60 (broadd, J=8.5 Hz, 2H); 8.10 (s, 1H). Mass spectrum (ES): m/z=440 (MH⁺) basepeak.

3-Benzyloxy-4-(4-bromophenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1.5 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole and 7.1cm³ of a 1N solution of tetrabutylammonium fluoride in tetrahydrofuranand 50 cm³ of tetrahydrofuran. 0.93 g of3-benzyloxy-4-(4-bromophenyl)-1H-pyrazole is thus obtained in the formof a whitish powder. ¹H NMR spectrum (400 MHz)-δ in ppm-in DMSO-d6: 5.34(s, 2H); 7.35 (tt, J=1.5 and 7.5 Hz, 1H); 7.41 (broad t, J=7.5 Hz, 2H);from 7.47 to 7.54 (m, 4H); 7.66 (m, 2H); 8.13 (s, 1H); 12.2 (broad m,1H). Mass spectrum (EI): m/z=328 (M^(+.)), m/z=91 (C₇H₇ ⁺) base peak.

3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(4-bromophenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1.817 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-pyrazole, 2.41 g of4-bromophenylboronic acid, 2.54 g of tripotassium phosphate, and 0.421 gof dichlorobis(triphenylphosphine)palladium in 40 cm³ ofdimethoxyethane. After purification by chromatography, under a nitrogenpressure of 50 kPa, on a column of silica gel (particle size 20-45μ;diameter 4 cm; height 60 cm), eluting with a mixture of ethyl acetateand of cyclohexane (5/95 by volume), fractions 15 to 30 are combined,and concentrated to dryness under reduced pressure (3 kPa). 1.5 g of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-bromophenyl)-1H-pyrazole arethus obtained in the form of a yellow oil which crystallizes. ¹H NMRspectrum (300 MHz)-δ in ppm-in DMSO-d6 for 77% of the mixture: 2.42 (s,3H); 5.33 (s, 2H); from 7.33 to 7.50 (m, 7H); 7.59 (broad d, J=8.5 Hz,2H); 7.72 (broad d, J=8.5 Hz, 2H); 7.84 (m, 2H); 8.86 (s, 1H). Massspectrum (EI): m/z=48 (M^(+.)), m/z=327 [(M-C₇H₇SO₂)⁺], m/z=91 (C₇H₇ ⁺),base peak.

EXAMPLE 70 4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol

A mixture of 0.5 g of3-benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 0.5g of ammonium formate and 0.5 g of palladium-on-charcoal (at 10%) in 50cm³ of ethanol is stirred for 30 minutes, under an inert atmosphere, ata temperature close to 70° C. The reaction medium is then cooled to atemperature close to 20° C., filtered through Celite®, rinsed withethanol and concentrated to dryness under reduced pressure (3 kPa). Theresidue is purified on a cartridge of silica (particle size 20-40 μm),eluting with a mixture of dichloromethane and of a 2N solution ofammoniacal methanol (90/10 by volume). 0.258 g of4-(1H-indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol is obtainedin the form of a flaky white solid. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.33 to 1.55 (m, 6H); 2.40 (m, 4H); 2.66 (t, J=6.5Hz, 2H); 4.00 (t, J=6.5 Hz, 2H); 6.39 (broad t, J=2.5 Hz, 1H); from 7.27to 7.40 (m, 3H); 7.81 (m, 2H); 10.05 (broad s, 1H); 10.95 (broad m, 1H).IR spectrum, KBr: 3265; 2944; 1593; 1524; 1242; 1184; 1044; 891; 803;762; 725 and 437 cm⁻¹. Mass spectrum (EI): m/z=310 (M^(+.)), m/z=98(C₆H₁₂N⁺) base peak.

3-Benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidin-1-ylethyl)-1-H-pyrazole

The procedure is carried out as in example 37, but with 3.39 g of3-benzyloxy-4-bromo-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 3.14 g of5-indolylboronic acid, 3.87 g of potassium carbonate, 1.2 g oftetrakis-(triphenyl)phosphine palladium in 70 cm³ of toluene and 20 cm³of ethanol. After purification twice on a cartridge of silica (particlesize 20-40 μm), eluting with a mixture of dichloromethane and ofmethanol (95/5 by volume), 2.17 g of3-benzyloxy-4-(1H-indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole isthus obtained in the form of a beige oil which crystallizes. ¹H NMRspectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.33 to 1.55 (m, 6H); from2.32 to 2.50 (broad m, 4H); 2.72 (broad m, 2H); 4.10 (t, J=6.5 Hz, 2H);5.32 (s, 2H); 6.39 (broad t, J=2.5 Hz, 1H); from 7.29 to 7.46 (m, 6H);7.52 (broad d, J=8.5 Hz, 2H); 7.81 (broad s, 1H); 7.93 (s, 1H); 11.0(broad m, 1H).

EXAMPLE 714-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol

The procedure is carried out as in example 38, but with 0.592 g of3-benzyloxy-4-(5-bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,3.65 cm³ of 12N hydrochloric acid and 4 cm³ of ethanol. The mixture isheated for 2 hours at a temperature close to 100° C. After cooling to atemperature close to 20° C., the reaction medium is taken up withethanol, and concentrated to dryness under reduced pressure (2 kPa); theresidue is precipitated from diisopropyl ether and then purified on acartridge of silica (particle size 20-40 μm), eluting with a mixture ofdichloromethane and of a 2N ammoniacal methanol solution (90/10 byvolume). 0.068 g of4-(5-bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole-3-ol isobtained in the form of a yellow powder. ¹H NMR spectrum (300 MHz)—δ inppm-in DMSO-d6: from 1.33 to 1.53 (m, 6H); 2.37 (m, 4H); 2.62 (t, J=6.5Hz, 2H); 3.99 (t, J=6.5 Hz, 2H); 6.93 (d, J=3.5 Hz, 1H); 7.10 (d, J=3.5Hz, 1H); 7.85 (s, 1H); from 10.45 to 10.75 (very broad m, 1H). IRspectrum, KBr: 2938; 1593; 1536; 1471; 1173; 981; 798; 758 and 496 cm⁻¹.Mass spectrum (EI): m/z=355 (M^(+.)), m/z=98 (C₆H₁₂N⁺) base peak.

3-Benzyloxy-4-(5-bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleoxalate

The procedure is carried out as in example 15, but with 0.154 g ofsodium hydride (75% by mass in liquid petroleum jelly), 0.477 g of1-(2-chloroethyl)-piperidine hydrochloride and 0.62 g of3-benzyloxy-4-(5-bromothiophen-2-yl)pyrazole in 13 cm³ ofdimethylformamide. After stirring for 1 hour at a temperature close to20° C., the medium is taken up with 50 cm³ of ethyl acetate and 50 cm³of water; the organic phase is separated by settling out, washed with 3times 50 cm³ of a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure (3 kPa). The residue is taken up with 10 cm³ of acetone and 170mg of oxalic acid in solution in 2 cm³ of acetone. The precipitate isfiltered through sintered glass, washed with acetone, dried, and thenpurified on a cartridge of silica (particle size 20-40 μm), eluting witha mixture of dichloromethane and of methanol (95/5 then 90/10 byvolume). 0.716 g of3-benzyloxy-4-(5-bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleoxalate is thus obtained in the form of a yellow powder. ¹H NMR spectrum(300 MHz)-δ in ppm-in DMSO-d6: 1.48 (m, 2H); 1.65 (m, 4H); from 2.86 to3.00 (broad m, 4H); 3.25 (broad partially masked m, 2H); 4.30 (broad t,J=6.5 Hz, 2H); 5.32 (s, 2H); 7.01 (d, J=3.5 Hz, 1H); 7.15 (d, J=3.5 Hz,1H); from 7.32 to 7.54 (m, 5H); 8.09 (s, 1H). IR spectrum, KBr: 2948;2536; 1724; 1641; 1595; 1532; 1498; 1451; 1363; 1173; 1008; 795 and 702cm⁻¹. Mass spectrum (EI): m/z=445 (M^(+.)), m/z=98 (C₆H₁₂N⁺) base peak.

3-Benzyloxy-4-(5-bromothiophen-2-yl)pyrazole

The procedure is carried out as in example 38, but with 1.1 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophen-2-yl)-1H-pyrazoleand 5 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran and 40 cm³ of tetrahydrofuran. After purification on acartridge of silica (particle size 20-40 μm), eluting with a mixture ofdichloromethane and acetone (95/5 by volume), 0.624 g of3-benzyloxy-4-(5-bromothiophen-2-yl)-1H-pyrazole is thus obtained in theform of a yellow solid. IR spectrum, KBr: 3193; 1599; 1503; 1438; 1362;1238; 1023; 795; 731; 694 and 496 cm⁻¹. Mass spectrum (EI): m/z=334(M^(+.)), m/z=91 (C₇H₇ ⁺) base peak.

1-(Toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophen-2-yl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-pyrazole, 1.32 g of5-bromothiophen-2-ylboronic acid, 1.22 g of potassium carbonate and 309mg of dichlorobis(triphenylphosphine)palladium in 20 cm³ of toluene and5 cm³ of ethanol. After purification on a cartridge of silica (particlesize 20-40 μm), eluting with a mixture of ethyl acetate and ofcyclohexane (10/90 by volume), 0.85 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(5-bromothiophen-2-yl)-1H-pyrazoleis thus obtained in the form of an orange gum. IR spectrum, CCl₄: 1597;1527; 1494; 1391; 1190; 1179; 1096; 1081; 695; 671; 595 and 540 cm¹.Mass spectrum (CI): m/z=489 (M⁺), m/z=263 (HPPh₃) base peak.

EXAMPLE 72 2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide

0.373 g of 4-(4-cyanophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleoxalate and 11 cm³ of 0.1N sodium hydroxide in 20 cm³ of dichloromethaneare stirred at a temperature close to 20° C. for 15 minutes. The organicphase is separated by settling out, dried over anhydrous magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure (3kPa). The residue is taken up with 11 cm³ of toluene. 0.287 g ofpotassium trimethylsilanolate is added and the reaction medium is heatedat the reflux of the solvent for 6 h 30 min. The mixture is cooled to atemperature close to 20° C., and taken up with 40 cm³ of ethyl acetateand 40 cm³ of water. The organic phase is separated by settling out,washed with water, dried over anhydrous magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure (3 kPa). The residue ispurified on a cartridge of silica (particle size 20-40 μm), eluting witha mixture of dichloromethane and a 2N ammoniacal methanol solution (95/5by volume). 0.081 g of2-[1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide is obtained inthe form of a white solid which melts at 168° C.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.33 to 1.55 (m,6H); 2.40 (m, 4H); 2.68 (t, J=6.5 Hz, 2H); 4.22 (t, J=6.5 Hz, 2H); from7.23 to 7.45 (m, 4H); 7.50 (broad d, J=8.5 Hz, 1H); 7.70 (d, J=1.0 Hz,1H); 7.75 (broad m, 1H); 7.98 (d, J=1.0 Hz, 1H). IR spectrum, KBr: 3380;3162; 2921; 1646; 1402; 954; 858; 754 and 633 cm⁻¹. Mass spectrum (CI):m/z=299 (MH⁺) base peak.

4-(4-Cyanophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate

The procedure is carried out as in example 15, but with 0.098 g ofsodium hydride (at 75% by mass in liquid petroleum jelly), 0.305 g of1-(2-chloroethyl)-piperidine hydrochloride and 0.2 g of4-(4-cyanophenyl)-1H-pyrazole. 0.373 g of4-(4-cyanophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate is thusobtained in the form of a white powder. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6:

1.50 (m, 2H); 1.68 (m, 4H); 2.96 (m, 4H); 3.33 (broad t, J=6.5 Hz, 2H);4.55 (t, J=6.5 Hz, 2H); 7.45 (m, 1H); 7.73 (m, 2H); 7.89 (m, 1H); 8.06(d, J=1.0 Hz, 1H); 8.42 (d, J=1.0 Hz, 1H). IR spectrum, KBr: 2949; 2223;1747; 1641; 1600; 1225; 1207; 990; 952; 764; 705 and 504 cm⁻¹. Massspectrum (CI): m/z=281 (MH⁺) base peak.

4-(4-Cyanophenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 0.613 g of1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole and 3.8 cm³ of a 1Nsolution of tetrabutylammonium fluoride in tetrahydrofuran and 30 cm³ oftetrahydrofuran. After purification on a cartridge of silica (particlesize 20-40 μm), eluting with a mixture of dichloromethane and of acetone(90/10 by volume), 0.202 g of 4-(4-cyanophenyl)-1H-pyrazole is thusobtained in the form of a white solid. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: 7.43 (m, 1H); from 7.69 to 7.80 (m, 2H); 7.88 (m, 1H);from 8.00 to 8.30 (broad m, 2H); 13.3 (broad m, 1H). IR spectrum, KBr:3153; 2966; 2218; 1601; 1516; 1347; 1044; 949; 763; 656 and 501 cm⁻¹.Mass spectrum (EI): m/z=169 (M^(+.)) base peak, m/z=142 [(M-CHN)⁺],m/z=115 [(m/z=142-CHN)⁺].

1-(Toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole

The procedure is carried out as in example 41 for the preparation of3-benzyloxy-4-(5-chlorothiophen-1-yl)-1-(toluene-4-sulfonyl)-1H-pyrazole,but using 0.943 g of1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole, 0.43 g of2-cyano-1-iodobenzene, 84 mg of tris(dibenzylideneacetone)palladium and77 mg of tris(trifuryl)phosphine in 11 cm³ of dioxane. Afterpurification on a cartridge of silica (particle size 20-40 μm), elutingwith a mixture of cyclohexane and of ethyl acetate (90/10 then 80/20then 50/50 by volume), 0.613 g of1-(toluene-4-sulfonyl)-4-(4-cyanophenyl)-1H-pyrazole is thus obtained inthe form of an orange-yellow pasty solid. ¹H NMR spectrum (400 MHz)-δ inppm-in DMSO-d6: 2.42 (s, 3H); from 7.50 to 7.58 (m, 3H); 7.78 (dt, J=1.5and 8.0 Hz, 1H); 7.84 (broad d, J=8.0 Hz, 1H); from 7.93 to 7.98 (m,3H); 8.38 (d, J=1.0 Hz, 1H); 8.98 (d, J=1.0 Hz, 1H). IR spectrum, KBr:2225; 1382; 1192; 1176; 1091; 1051; 812; 761; 702; 679; 664; 593 and 541cm⁻¹. Mass spectrum (EI): m/z=323 (M^(+.)), m/z=259 [(M-SO₂)^(+.)],m/z=91 (C₇H₇ ⁺) base peak.

1-(Toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole

The procedure is carried out as in example 41 for the preparation of3-benzyloxy-1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole, butusing 1.5 g of 1-(toluene-4-sulfonyl)-4-iodo-1H-pyrazole, 2.65 cm³ of1,1,1,2,2,2-hexabutyldistannane, 58 mg of palladium diacetate and 136 mgof triphenylphosphine in 20 cm³ of DMF. After 2 purifications on acartridge of silica (particle size 20-40 μm), eluting with cyclohexaneand then a mixture of cyclohexane and of ethyl acetate (95/5 by volume),0.743 g of 1-(toluene-4-sulfonyl)-4-tributylstannanyl-1H-pyrazole isthus obtained in the form of a colorless oil. IR spectrum, CH₂Cl₂: 2959;2925; 2873; 2854; 1378; 1175; 1064; 957; 673; 594 and 543 cm⁻¹. Massspectrum (EI): m/z=511 (M^(+.)), m/z=455 [(M-C₄H₈)^(+.)] base peak,m/z=399 [(m/z=455-C₄H₈)^(+.)], m/z=343 [(m/z=399-C₄H₈)^(+.)], m/z=91(C₇H₇ ⁺).

EXAMPLE 73 4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazolehydrochloride

A stirred solution of 0.582 g of4-(2-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate in 12cm³ of dichloromethane, under an inert atmosphere, is cooled to atemperature close to −78° C. 4.3 cm³ of boron tribromide are added andthe stirring is continued for 4 hours at a temperature close to −70° C.,and then for 15 hours at a temperature close to 20° C. The reactionmedium is taken up with 10 cm³ of water. The organic phase is separatedby settling out and then washed with a 1N sodium hydroxide solutionuntil a pH of 8-8.4 (Lyphan paper) is obtained, and taken up with 20 cm³of water. The organic phase is separated by settling out, dried overanhydrous magnesium sulfate, filtered, and concentrated to dryness underreduced pressure (3 kPa). The residue is precipitated from diisopropylether; the precipitate is purified on a cartridge of silica (particlesize 20-40 μm), eluting with a mixture of dichloromethane and ofmethanol (90/10 by volume); the gum obtained is taken up with a 1Nhydrochloric diethyl ether solution. 0.172 g of4-(2-hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole hydrochlorideis obtained in the form of a pink powder. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.30 to 1.82 (broad m, 6H); from 2.38 to 3.62 (verybroad m, 6H); from 4.22 to 4.60 (broad m, 2H); 6.82 (dt, J=1.5 and 8.0Hz, 1H); 6.92 (broad d, J=8.0 Hz, 1H); 7.03 (dt, J=1.5 and 8.0 Hz, 1H);7.54 (dd, J=1.5 and 8.0 Hz, 1H); 7.98 (broad s, 1H); 8.23 (broad s, 1H);from 9.05 to 9.45 (very broad m, 1H); 9.76 (broad s, 1H). IR spectrum,KBr: 3144; 2938; 2539; 1560; 1461; 1351; 1282; 1238; 1111; 954; 856; 747and 478 cm⁻¹. Mass spectrum (EI): m/z=271 (M^(+.)), m/z=98 [C₆H₁₂N⁺]base peak.

4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate

The procedure is carried out as in example 15, but with 0.22 mg ofsodium hydride (at 75% by mass in liquid petroleum jelly), 0.681 g of1-(2-chloroethyl)-piperidine hydrochloride and 0.46 mg of4-(2-methoxyphenyl)-1H-pyrazole. 0.582 g of4-(2-methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole oxalate isthus obtained in the form of a white solid. ¹H NMR spectrum (300 MHz)-δin ppm-in DMSO-d6 for 50% of the mixture: 1.50 (m, 2H); from 1.62 to1.75 (broad m, 4H); from 2.88 to 3.09 (m, 4H); 3.15 (t, J=6.5 Hz, 2H);3.89 (s, 3H); 4.52 (t, J=6.5 Hz, 2H); 6.99 (broad t, J=8.0 Hz, 1H); 7.10(broad d, J=8.0 Hz, 1H); 7.23 (dt, J=1.5 and 8.0 Hz, 1H); 7.63 (dd,J=1.5 and 8.0 Hz, 1H); 8.01 (broad s, 1H); 8.23 (broad s, 1H). IRspectrum, KBr: 2948; 2537; 1719; 1635; 1493; 1246; 1184; 1028; 952; 756;721; 704 and 497 cm⁻¹. Mass spectrum (CI): m/z=281 (MH⁺) base peak,m/z=148 (M′H⁺).

4-(2-Methoxyphenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1.08 g of1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole and 7.3 cm³ of a1N solution of tetrabutylammonium fluoride in tetrahydrofuran and 58 cm³of tetrahydrofuran. After purification on a cartridge of silica(particle size 20-40 μm), eluting with a mixture of dichloromethane andof methanol (90/10 by volume), 0.463 g of4-(2-methoxyphenyl)-1H-pyrazole is thus obtained in the form of anoff-white solid. ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 3.89 (s,3H); 6.97 (dt, J=1.5 and 8.5 Hz, 1H); 7.06 (broad d, J=8.5 Hz, 1H); 7.21(m, 1H); 7.63 (dd, J=1.5 and 8.5 Hz, 1H); from 7.85 to 8.20 (very broadm, 2H); 12.9 (broad m, 1H). IR spectrum, KBr: 3156; 2936; 2832; 1569;1488; 1466; 1263; 1247; 1148; 1027; 950; 753; 661 and 628 cm⁻¹. Massspectrum (EI): m/z=174 (M^(+.)) base peak, m/z=159 [(M-CH₃)⁺], m/z=131[(m/z=159-CO)⁺].

1-(Toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1.5 g of1-(toluene-4-sulfonyl)-4-iodo-1H-pyrazole, 1.31 g of2-methoxyphenylboronic acid, 1.74 g of potassium carbonate and 0.605 gof dichlorobis(triphenylphosphine)palladium in 30 cm³ of toluene and 7.5cm³ of ethanol. After purification on a cartridge of silica (particlesize 20-40 μm), eluting with a mixture of ethyl acetate and ofcyclohexane (20/80 by volume), 1.081 g of1-(toluene-4-sulfonyl)-4-(2-methoxyphenyl)-1H-pyrazole are thus obtainedin the form of an orange gum. ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: 2.41 (s, 3H); 3.92 (s, 3H); 7.01 (dt, J=1.5 and 8.5 Hz, 1H);7.13 (broad d, J=8.5 Hz, 1H); 7.33 (m, 1H); broad d, J=8.5 Hz, 2H); 7.73(dd, J=1.5 and 8.5 Hz, 1H); 7.93 (broad d, J=8.5 Hz, 2H); 8.41 (broad s,1H); 8.72 (broad s, 1H). IR spectrum, KBr: 2835; 1497; 1371; 1177; 1097;1039; 1023; 950; 753; 681; 598 and 550 cm⁻¹. Mass spectrum (EI): m/z=328(M^(+.)) base peak, m/z=264 [(M-SO₂)^(+.)], m/z=173 [(M-C₇H₇SO₂)⁺],m/z=91 (C₇H₇ ⁺).

EXAMPLE 74 4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1.22 g of4-iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole, 1.93 g of1H-indol-5-ylboronic acid, 2.547 g of tripotassium phosphate, 0.421 g ofdichlorobis(triphenylphosphine)palladium in 50 cm³ of dimethoxyethane.After purification by chromatography, under a nitrogen pressure of 50kPa, on a column of silica gel (particle size 20-45μ; diameter 3 cm;height 60 cm), eluting with a mixture of ethyl acetate and of methanol(95/5 then 90/10 by volume), fractions 18 to 30 are combined, andconcentrated to dryness under reduced pressure (3 kPa). 0.23 g of4-(1H-indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole is thus obtainedin the form of a whitish powder. ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: from 1.34 to 1.56 (m, 6H); 2.41 (m, 4H); 2.72 (t, J=6.5 Hz,2H); 4.22 (t, J=6.5 Hz, 2H); 6.41 (m, 1H); from 7.27 to 7.40 (m, 3H);7.71 (m, 1H); 7.80 (d, J=1.0 Hz, 1H); 8.06 (broad s, 1H); 11.0 (broad m,1H).

IR spectrum, KBr: 2937; 1436; 1363; 1167; 1119; 994; 887; 792; 763; 614and 430 cm⁻¹.

Mass spectrum (EI): m/z=294 (M^(+.)), m/z=98 (C₆H₁₂N⁺) base peak.

4-Iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole

The procedure is carried out as in example 15, but with 4.94 g of sodiumhydride (at 75% by mass in liquid petroleum jelly), 19 g of1-(2-chloroethyl)piperidine hydrochloride and 10 g of 4-iodopyrazole.After stirring for 16 hours at a temperature close to 20° C., thereaction medium is taken up with 1000 cm³ of ethyl acetate and 1000 cm³of water; the organic phase is separated by settling out, washed with 3times 1000 cm³ of water and 500 cm³ of a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure (3 kPa). The residue ispurified by chromatography, under a nitrogen pressure of 50 kPa, on acolumn of silica gel (particle size 20-45μ; diameter 6 cm; height 60cm), eluting with a mixture of ethyl acetate and of cyclohexane (30/70by volume) and then ethyl acetate. Fractions 16 to 20 are combined, andconcentrated to dryness under reduced pressure (3 kPa). 8.2 g of4-iodo-1-(2-piperidin-1-ylethyl)-1H-pyrazole are thus obtained in theform of a light yellow oil. ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: from 1.34 to 1.52 (m, 6H); 2.36 (m, 4H); 2.64 (t, J=6.5 Hz,2H); 4.22 (t, J=6.5 Hz, 2H); 7.51 (broad s, 1H); 7.92 (broad s, 1H).Mass spectrum (CI): m/z=306 (MH⁺) base peak.

EXAMPLE 75 4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

The procedure is carried out as in example 38, but with 0.63 g of3-benzyloxy-4-(4-methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole,4.8 cm³ of 12N hydrochloric acid and 4.8 cm³ of ethanol. The mixture isheated for 4 hours at a temperature close to 100° C. After cooling to atemperature close to 20° C., the reaction medium is taken up withethanol, and concentrated to dryness under reduced pressure (2 kPa); theresidue is precipitated from diisopropyl ether. 0.385 g of4-(4-methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride is obtained in the form of a white solid. ¹H NMR spectrum(300 MHz)-δ in ppm-in DMSO-d6: 1.40 (m, 1H); from 1.63 to 1.87 (m, 5H);2.30 (s, 3H); from 2.82 to 3.02 (broad m, 2H); from 3.27 to 3.53 (m,4H); 4.38 (broad t, J=6.5 Hz, 2H); 7.15 (broad d, J=8.5 Hz, 2H); 7.54(broad d, J=8.5 Hz, 2H); 7.98 (s, 1H); 10.05 (very broad m, 1H); 10.4(broad m, 1H). IR spectrum, KBr: 2941; 2646; 1597; 1534; 1447; 1179;1010; 818; 627 and 515 cm⁻¹. Mass spectrum (EI): m/z=285 (M^(+.)),m/z=98 (C₆H₁₂N⁺) base peak.

3-Benzyloxy-4-(4-methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleoxalate

The procedure is carried out as in example 15, but with 0.123 g ofsodium hydride (at 75% by mass in liquid petroleum jelly), 0.38 g of1-(2-chloroethyl)piperidine hydrochloride and 0.39 g of3-benzyloxy-4-(4-methylphenyl)pyrazole. 0.632 g of3-benzyloxy-4-(4-methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazoleoxalate is thus obtained in the form of a white powder.

IR spectrum, KBr: 2931; 2639; 2543; 1719; 1618; 1580; 1519; 1452; 1279;1180; 818; 721 and 500 cm⁻¹. Mass spectrum (CI): m/z=376 (MH⁺) basepeak.

3-Benzyloxy-4-(4-methylphenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 0.8 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-(4-methylphenyl)-1H-pyrazole and 4cm³ of a 1N solution of tetrabutylammonium fluoride in tetrahydrofuranand 40 cm³ of tetrahydrofuran. 0.397 g of3-benzyloxy-4-(4-methylphenyl)-1H-pyrazole is thus obtained in the formof a white powder. IR spectrum, KBr: 3187; 2980; 1586; 1498; 1450; 1380;1233; 1043; 814; 737; 695 and 514 cm⁻¹. Mass spectrum (EI): m/z=264(M^(+.)), m/z=186 [(M-C₆H₆)^(+.)], m/z=91 (C₇H₇+) base peak.

3-Benzyloxy-1-(toluene-4-sulfonyl)-4-(4-methylphenyl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1 g of1-(toluene-4-sulfonyl)-3-benzyloxy-4-iodo-1H-pyrazole, 0.898 g of4-methylphenylboronic acid, 0.913 g of potassium carbonate and 0.331 gof tetrakis(triphenylphosphine)palladium in 13 cm³ of toluene, 3 cm³ ofethanol and 3.3 cm³ of water. 0.817 g of3-benzyloxy-1-(toluene-4-sulfonyl)-4-(4-methylphenyl)-1H-pyrazole isthus obtained in the form of a pinkist-beige cottonwool-like solid. IRspectrum, KBr: 1589; 1485; 1377; 1191; 1179; 1098; 813; 702; 672; 580and 538 cm⁻¹. Mass spectrum (EI): m/z=418 (M^(+.)), m/z=263[(M-C₇H₇SO₂)⁺], m/z=91 (C₇H₇ ⁺) base peak.

EXAMPLE 76 1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole

The procedure is carried out as in example 38, but with 1 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-pyrazole, 0.797 g of1H-indol-5-ylboronic acid, 1.026 g of potassium carbonate, 0.463 g ofdichlorobis(triphenylphosphine)palladium in 30 cm³ of toluene, 6 cm³ ofethanol and 3 cm³ of water. After purification by chromatography, undera nitrogen pressure of 50 kPa, on an alumina CTB1 column, eluting withethyl acetate and then a mixture of ethyl acetate and of methanol (95/5then 90/10 then 80/20 by volume), fractions 97 to 110 are combined, andconcentrated to dryness under reduced pressure (3 kPa). The residue isprecipitated from a mixture of 5 cm³ of ethyl acetate and 25 cm³ ofdiisopropyl ether. 0.18 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole is thusobtained in the form of a yellow powder. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: 1.34 (m, 1H); from 1.53 to 1.75 (m, 3H); 2.13 (m, 1H);from 2.67 to 2.81 (m, 3H); 3.02 (m, 1H); 3.26 (partially masked m, 1H);3.49 (m, 1H); 4.44 (m, 1H); 6.40 (m, 1H); from 7.29 to 7.41 (m, 3H);7.75 (broad s, 1H); 7.87 (broad s, 1H); 8.22 (broad s, 1H); 11.0 (broadm, 1H). IR spectrum, KBr: 3113; 2939; 1587; 1454; 1362; 1165; 1058; 976;881; 792; 729; 619 and 435 cm⁻¹. Mass spectrum (ES): m/z=293 (MH⁺) basepeak.

The enantiomers are separated by HPLC on chiralpak AD 20 μm with, aseluent, a mixture of heptane, of ethanol and of butylamine (40/60/0.2 byvolume). Two enantiomers, A and B, are obtained, which are purifiedaccording to the following protocol: enantiomer A is purified byextraction with ethyl acetate and then solubilized in 100 ml of water.The pH of the solution is adjusted to 10 with 0.1N sodium hydroxide. Theorganic phase is extracted with 100 ml of ethyl acetate. The aqueousphase is separated by settling out with 2×50 ml of dichloromethane. Theorganic phase is dried with anhydrous sodium sulfate, filtered, andconcentrated to dryness under reduced pressure. The organic phase iscontrolled by reverse-phase polarity HPLC on a Thermo hypersil HypurityC18 250*4.6*5 μm column; eluent: 95/5 gradient: acetatebuffer/acetonitrile for 50 minutes. 42.6 mg of(−)-1-(1-azabicyclo-[2.2.2]oct-3-yl)-4-(1H-indol-5yl)-1H-pyrazole,enantiomer A are obtained ([α]²⁰ _(D)=−37.3° (solvent: dimethylsulfoxide, concentration: 0.3)).

Enantiomer B is purified by extraction with ethyl acetate and thensolubilized in 100 ml of water. The pH of the solution is adjusted to 10with 0.1N sodium hydroxide. The organic phase is extracted with 100 mlof ethyl acetate. The aqueous phase is separated by settling out with2×50 ml of dichloromethane. The organic phase is dried with anhydroussodium sulfate, filtered, and concentrated to dryness under reducedpressure. The organic phase is controlled by reverse-phase polarity HPLCon a Thermo hypersil Hypurity C18 250*4.6*5 μm column; eluent: 95/5gradient: acetate buffer/acetonitrile for 50 minutes. 56.3 mg of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-5-yl)-1H-pyrazole,enantiomer B are obtained ([α]²⁰ _(D)=+36.2° (solvent: dimethylsulfoxide, concentration: 0.42)).

1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-pyrazole

The procedure is carried out as in example 5, but with 0.48 g of sodiumhydride (at 75% by mass in liquid petroleum jelly), 3.079 g oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester and 1.94 g of4-iodopyrazole in 30 cm³ of dimethylformamide. The residue is purifiedby chromatography, under a nitrogen pressure of 50 kPa, on an aluminaCBT1 column, eluting with ethyl acetate and then a mixture of ethylacetate and of methanol (95/5 then 90/10 by volume). Fractions 29 to 39are combined, and concentrated to dryness under reduced pressure (3kPa). The oil obtained is again purified on an alumina CBT1 column,eluting with ethyl acetate. Fractions 11 to 15 are combined, andconcentrated to dryness under reduced pressure (3 kPa). 0.33 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-pyrazole is obtained in theform of an oil which crystallizes. ¹H NMR spectrum (400 MHz)-δ in ppm-inDMSO-d6: 1.30 (m, 1H); 1.46 (m, 1H); 1.66 (m, 2H); 2.05 (m, 1H); from2.65 to 2.78 (m, 4H); 2.91 (m, 1H); 3.21 (partially masked m, 1H); 4.44(m, 1H); 7.58 (broad s, 1H); 8.06 (broad s, 1H). Mass spectrum (EI):m/z=303 (M^(+.)), m/z=220 [(M-C₅H₉N)^(+.)], m/z=109 (C₇H₁₁N^(+.)),m/z=97 (C₆H₁₁N^(+.)) base peak.

EXAMPLE 771-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-olhydrochloride, Isomer A

The procedure is carried out as in example 38, but with 0.13 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole,isomer A, 10 cm³ of 12N hydrochloric acid and 15 cm³ of ethanol. Themixture is heated for 22 hours at a temperature close to 100° C., andthen cooled to a temperature close to 20° C.; the reaction medium isconcentrated to dryness under reduced pressure (3 kPa), then taken upwith twice 20 cm³ of ethanol and concentrated to dryness under reducedpressure (2 kPa); the residue is precipitated from 20 cm³ of diisopropylether. 80 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-olhydrochloride, isomer A, are obtained in the form of a grayish powder.¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.62 to 1.98 (m,4H); 2.36 (m, 1H); from 3.07 to 3.55 (partially masked m, 4H); 3.71 (m,2H); 4.62 (m, 1H); 7.03 (m, 2H); 8.10 (broad s, 1H); 10.75 (broad m,1H).

IR spectrum, KBr: 1602; 1536; 1459; 1164; 1005; 795 and 502 cm⁻¹.

Mass spectrum (ES): m/z=310 (MH⁺) base peak. [α]_(D)=−14° (solvent:MeOH, concentration 0.1266).

EXAMPLE 781-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazol-3-olhydrochloride, Isomer B

The procedure is carried out as in example 38, but with 0.13 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole,isomer B, 5 cm³ of 12N hydrochloric acid and 10 cm³ of ethanol. Themixture is heated for 16 hours at a temperature close to 100° C., thencooled to a temperature close to 20° C.; the reaction medium isconcentrated to dryness under reduced pressure (3 kPa), then taken upwith twice 20 cm³ of toluene and concentrated to dryness under reducedpressure (2 kPa); the residue is taken up with 3 times 20 cm³ of ethanoland concentrated to dryness under reduced pressure (2 kPa). The residuethus obtained is precipitated from 20 cm³ of diisopropyl ether. 100 mgof1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(5-chlorothiophen-2-yl)-1H-pyrazole-3-olhydrochloride, isomer B, are obtained in the form of a grayish powder.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.62 to 2.00 (m,4H); 2.38 (m, 1H); from 3.05 to 3.53 (m, 4H); 3.73 (m, 2H); 4.63 (m,1H); 7.03 (m, 2H); 8.11 (broad s, 1H); 10.75 (broad m, 1H). IR spectrum,KBr: 1601; 1536; 1457; 1163; 1004; 794 and 502 cm⁻¹. Mass spectrum (CI):m/z=310 (MH⁺) base peak. [α]_(D)=−18° (solvent: MeOH, concentration:0.2168).

1-(1-Azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole,Isomers A and B

The procedure is carried out as in example 5, but with 0.495 g of sodiumhydride (at 75% by mass in liquid petroleum jelly), 3.178 g oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]oct-3-yl ester and 1.94 g of3-benzyloxy-4-(5-chlorothiophen-2-yl)pyrazole in 70 cm³ ofdimethylformamide. The residue is purified by chromatography, under anitrogen pressure of 50 kPa, on a column of silica gel (particle size20-45μ; diameter 3 cm; height 50 cm), eluting with dichloromethane andthen a mixture of dichloromethane and of methanol (95/5 then 90/10 then80/20 by volume). Fractions 52 to 74 are combined, and concentrated todryness under reduced pressure (3 kPa). The oil obtained is againpurified on an alumina CBT1 column, eluting with ethyl acetate and thena mixture of ethyl acetate and of methanol (90/10 by volume). Fractions22, 32 and 40 to 50 are combined, and concentrated to dryness underreduced pressure (3 kPa). 0.5 g of1-(1-azabicyclo[2.2.2]-oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazoleis thus obtained in the form of a green oil which crystallizes, forwhich the two enantiomers are separated by HPLC.

Mass spectrum (EI): m/z=399 (M^(+.)), m/z=308 [(M-C₇H₇)⁺], m/z=110(C₇H₁₂N⁺), m/z=91 (C₇H₇ ⁺) base peak.

Using 0.45 g of1-(1-aza-bicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole,the enantiomers are separated by HPLC on chiralpak AD 20 μm, elutingwith a mixture of 70% heptane/15% ethanol/15% methanol/0.1%triethylamine. 138 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiophen-2-yl)-1H-pyrazole,isomer A ([α]D=+28.2° (solvent: MeOH, concentration: 0.5)) and 129 mg of1-(1-azabicyclo[2.2.2]oct-3-yl)-3-benzyloxy-4-(5-chlorothiopen-2-yl)-1H-pyrazole,isomer B ([α]_(D)=−24.6° (solvent: MeOH, concentration: 0.5)) areobtained. Mass spectrum (IE): m/z=399 (M^(+.)), m/z=308 [(M-C₇H₇)⁺],m/z=110 (C₇H₁₂N⁺), m/z=91 (C₇H₇ ⁺) base peak.

EXAMPLE 791-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-olhydrochloride

1.8 cm³ of 6N hydrochloric acid is added to a solution of 0.8 g of2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane in20 cm³ of ethanol and the mixture is stirred at ambient temperature for30 minutes and then concentrated to dryness under reduced pressure (3kPa). The suspension of the residue obtained and of 114 mg ofpalladium-on-charcoal at 10% in 20 cm³ of ethanol is stirred in anautoclave under a hydrogen pressure of 100 kPa, at a temperature of 20°C. for 8 hours. The reaction medium is then filtered through Celite® andconcentrated to dryness under reduced pressure (3 kPa), to give a pastyresidue, which is covered with 40 cm³ of acetone and triturated untilcrystallization is complete. After filtration of the solid that hasappeared and drying under vacuum (70 Pa) at a temperature of 60° C., 0.6g of 1-(1-azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-olhydrochloride is obtained in the form of beige crystals which melt at atemperature above 260° C. ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6(referenced at 2.50 ppm): 1.55 (m, 1H); from 1.71 to 1.95 (m, 5H); 2.08(m, 1H); from 3.12 to 3.35 (partially masked m, 3H); 3.50 (m, 1H); 3.88(m, 1H); 4.27 (dd, J=7.5 and 14.0 Hz, 1H); 4.42 (dd, J=7.5 and 14.0 Hz,1H); 7.12 (broad t, J=7.5 Hz, 1H); 7.32 (broad t, J=7.5 Hz, 2H); 7.63(broad d, J=7.5 Hz, 2H); 8.01 (s, 1H); 9.80 (broad m, 1H); 10.45 (broadm, 1H). Mass spectrum (EI): m/z=283 (M^(+.)), m/z=201 [(M-C₅H₈N)^(+.)],m/z=173 [(M-C₇H₁₂N)^(+.)], m/z=124 (C₈H₁₄N⁺) base peak, m/z=82 (C₅H₈N⁺),m/z=36 (HCl^(+.)).

The 2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanecan be obtained in the following way:

182 mg of sodium hydride (at 75% by mass in liquid petroleum jelly) areadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.95 g of 3-benzyloxy-4-phenylpyrazole in 20 cm³ ofanhydrous dimethylformamide. After stirring for three-quarters of anhour at a temperature in the region of 50° C., a solution of 1.25 g of1-azabicyclo[2.2.2]oct-2-ylmethyl methanesulfonate in 20 cm³ ofanhydrous dimethylformamide is gradually added, and the mixture is thenheated for 24 hours at a temperature in the region of 110° C. Themixture is cooled to ambient temperature, and then 10 cm³ of water areslowly added and the mixture is finally concentrated in a rotaryevaporator. 25 cm³ of water are added to the residue obtained, which isextracted with 250 cm³ of ethyl acetate. The organic phase is washedwith 3 times 25 cm³ of water, then filtered through a phase-separatingfilter (Whatman®, reference: 2200 185) and concentrated to dryness underreduced pressure (3 kPa). The oily residue obtained is purified bychromatography on alumina, eluting with dichloromethane. Afterconcentrating the fractions under reduced pressure, 0.8 g of2-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane isobtained in the form of an oil which solidifies slowly as an amorphoussolid. Mass spectrum (EI): m/z=373 (M^(+.)), m/z=282 [(M-C₇H₇)⁺],m/z=124 (C₈H₁₄N⁺), m/z=91 (C₇H₇ ⁺) base peak, m/z=82 (C₅H₈N⁺).

The 1-azabicyclo[2.2.2]oct-2-ylmethyl methanesulfonate can be obtainedin the following way:

0.69 cm³ of pyridine followed, dropwise, by 0.66 cm³ of methanesulfonylchloride are added, at a temperature in the region of 0° C. and under anargon atmosphere, to a solution of 1 g of(1-azabicyclo[2.2.2]oct-2-yl)-methanol in 40 cm³ of dichloromethane. Thesuspension is stirred for 20 minutes at around 0° C. and then for 18hours at ambient temperature. 15 cm³ of a saturated potassium carbonatesolution are then added to the mixture, which is extracted with 3 times50 cm³ of ethyl acetate. The combined organic phases are dried overanhydrous magnesium sulfate, filtered, and concentrated to dryness underreduced pressure (3 kPa). The residue obtained is purified bychromatography on alumina, eluting with ethyl acetate. Afterconcentrating the fractions under reduced pressure, 1.1 g of1-azabicyclo[2.2.2]oct-2-ylmethyl methanesulfonate are obtained in theform of a colorless oil. Mass spectrum (EI): m/z=219 (M^(+.)), m/z=140[(M-SO₂CH₃)⁺], m/z=124 (C₈H₁₄N⁺) base peak.

The (1-azabicyclo[2.2.2]oct-2-yl)methanol can be obtained according tothe method described in patent DE 1938546.

EXAMPLE 803-[4-(3,5-Difluorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octanehydrochloride:

0.173 g of sodium hydride (at 75% by mass in liquid petroleum jelly) isadded gradually, under an argon atmosphere and at ambient temperature,to a solution of 0.65 g of 4-(3,5-difluorophenyl)-1H-pyrazole in 30 cm³of anhydrous dimethylformamide. After stirring for three-quarters of anhour at a temperature in the region of 50° C., a solution of 1.17 g of3-[(methanesulfonyl)oxy]-1-azabicyclo[2.2.2]octane in 10 cm³ ofanhydrous dimethylformamide is added dropwise, and the mixture is thenheated for 20 hours at a temperature in the region of 110° C. Themixture is cooled to ambient temperature, 5 cm³ of water are slowlyadded, and the mixture is concentrated under reduced pressure (3 kPa).The residue is taken up with 20 cm³ of water and extracted with 250 cm³of ethyl acetate. The organic phase is washed with 4 times 20 cm³ ofwater, then dried, filtered and concentrated to dryness under reducedpressure (3 kPa). The residue obtained is purified by chromatography onalumina, eluting with a mixture of dichloromethane and of ethyl acetate(70/30 by volume). After concentrating the fractions under reducedpressure, an oil is obtained, which is dissolved in 35 cm³ of acetoneand 20 cm³ of 1M hydrochloric ether are added. After stirring for 1 hourat ambient temperature, the solid which has appeared is isolated byfiltration and dried under vacuum (70 kPa) at a temperature of 40° C.0.44 g of3-[(4-(3,5-difluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanehydrochloride is thus obtained in the form of hygroscopic whitecrystals. ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6 (referenced at2.50 ppm): 1.71 (m, 2H); 2.00 (m, 2H); 2.42 (m, 1H); from 3.20 to 3.48(m, 4H); from 3.75 to 3.95 (m, 2H); 4.90 (m, 1H); 7.05 (tt, J=2.5 and9.5 Hz, 1H); 7.40 (m, 2H); 8.17 (broad s, 1H); 8.60 (broad s, 1H); 10.6(broad m, 1H). Mass spectrum (EI): m/z=289 (M^(+.)) base peak, m/z=206[(M-C₅H₉N)^(+.)], m/z=109 (C₇H₁₁N^(+.)), m/z=36 (HCl^(+.)).

The 4-(3,5-difluorophenyl)-1H-pyrazole can be obtained in the followingway:

15.7 cm³ of a solution of tetrabutylammonium fluoride in tetrahydrofuranat 1M are added, at ambient temperature, to a solution of 2.1 g of4-(3,5-difluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 70 cm³ oftetrahydrofuran. The mixture is refluxed for 4.5 hours, and then cooledto ambient temperature and concentrated to dryness under reducedpressure (3 kPa). 50 cm³ of water are added to the residue, which isextracted with 200 cm³ of ethyl acetate. The organic phase is washedwith 50 cm³ of water and then with 25 cm³ of brine, and is finally driedover anhydrous magnesium sulfate, filtered, and concentrated to drynessunder reduced pressure (3 kPa). The residue is triturated in 40 cm³ ofdichloromethane, and then isolated by filtration under vacuum. 0.65 g of4-(3,5-difluorophenyl)-1H-pyrazole is thus obtained in the form of whitecrystals which melt at around 185° C. Mass spectrum (EI): m/z=180(M^(+.)) base peak, m/z=153 [(M−HCN)⁺], m/z=126 [(m/z=153−HCN)^(+.)].

The 4-(3,5-difluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can beprepared in the following way:

6.31 g of 3,5-difluorophenylboronic acid are added, under an argonatmosphere and at ambient temperature, to a solution of 3.5 g of4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 100 cm³ of1,2-dimethoxyethane. The reaction medium is heated at 110° C. and 8.5 gof finely ground tribasic potassium phosphate and 0.91 g ofbis(triphenylphosphine)palladium chloride are then added and therefluxing is subsequently maintained for 3.5 hours. The mixture iscooled to ambient temperature, and filtered through Celite®, which isthen washed with 500 cm³ of ethyl acetate. The organic phase is washedwith 5 times 100 cm³ of water and then with twice 100 cm³ of brine,dried over anhydrous magnesium sulfate, filtered, and concentrated todryness under reduced pressure (3 kPa). The residue is purified bychromatography on silica, eluting with cyclohexane and thendichloromethane. After concentrating the fractions under reducedpressure, 2.2 g of4-(3,5-difluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are obtainedin the form of a white powder. Mass spectrum (EI): m/z=334 (M^(+.)),m/z=270 [(M-SO₂)^(+.)], m/z=155 (C₇H₇SO₂ ⁺), m/z=91 (C₇H₇ ⁺) base peak.

EXAMPLE 814-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride

8 cm³ of 12N hydrochloric acid are added to a stirred solution of 930 mgof1-[2-(4-benzo[b]thiophen-2-yl-3-benzyloxypyrazol-1-yl)ethyl]piperidinein 15 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue is,three times, successively dissolved in ethanol and evaporated to drynessunder reduced pressure (2.7 kPa) and is then triturated in 20 cm³ ofdiisopropyl ether. The precipitate formed is filtered off and driedunder reduced pressure (2.7 kPa), to give 790 mg of4-benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-olhydrochloride in the form of a pale yellow solid. Mass spectrum (CI):328(+)=(M+H)(+); presence 36(+)/38(+)=HCl(+). ¹H NMR spectrum (300MHz)-δ in ppm-in DMSO-d6: 1.42 (m, 1H); from 1.65 to 1.89 (m, 5H); 2.95(m, 2H); from 3.38 to 3.54 (m, 4H); 4.44 (t, J=6.5 Hz, 2H); from 7.23 to7.38 (m, 2H); 7.50 (s, 1H); 7.78 (broad d, J=7.5 Hz, 1H); 7.90 (broad d,J=7.5 Hz, 1H); 8.07 (s, 1H); from 10.05 to 10.2 (very broad m, 1H); 10.9(broad m, 1H).

The1-[2-(4-benzo[b]thiophen-2-yl-3-benzyloxypyrazol-1-yl)ethyl]piperidinecan be prepared in the following way:

860 mg of 4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-pyrazole are added,portionwise, to a suspension of 225 mg of sodium hydride (at 75% inliquid petroleum jelly) in 30 cm³ of dimethylformamide under an argonatmosphere and with stirring. After heating at 50° C. for 30 min, themixture is stirred for 1 h at a temperature in the region of 20° C., andthen 725 mg of 1-(2-chloroethyl)piperidine are added, portionwise,thereto. The reaction medium is stirred for 15 h at a temperature in theregion of 20° C., and is then poured into 100 cm³ of water. The aqueousphase is extracted twice with ethyl acetate. The organic phases arecombined, washed successively with two times water and a saturatedaqueous sodium chloride solution, dried over magnesium sulfate,filtered, and evaporated under reduced pressure (2.7 kPa), to give ayellow oil which is purified by flash chromatography on alumina CBT1under an argon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate(95/5 by volume)]. After concentrating the fractions under reducedpressure, 930 mg of1-[2-(4-benzo[b]thiophen-2-yl-3-benzyloxypyrazol-1-yl)ethyl]-piperidineare obtained in the form of a pale yellow oil. ¹H NMR spectrum (300MHz)-δ in ppm-in DMSO-d6: from 1.34 to 1.54 (m, 6H); 2.40 (m, 4H); 2.69(t, J=6.5 Hz, 2H); 4.11 (t, J=6.5 Hz, 2H); 5.37 (s, 2H); from 7.23 to7.48 (m, 6H); 7.56 (broad d, J=8.5 Hz, 2H); 7.73 (broad d, J=7.5 Hz,1H); 7.90 (broad d, J=7.5 Hz, 1H); 8.10 (s, 1H).

The 4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-pyrazole can be prepared inthe following way:

7.6 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 1.4 g of4-benzo[b]thiophen-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazolein 30 cm³ of tetrahydrofuran. After heating for 15 h at the reflux ofthe solvent, the reaction medium is evaporated under reduced pressure(2.7 kPa) and ethyl acetate is added to the residue. The organic phaseis washed successively with two times water and a saturated aqueoussodium chloride solution; it is dried over magnesium sulfate andevaporated under reduced pressure (2.7 kPa). The pale yellow oilobtained (0.98 g) is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (70/30 byvolume)]. After concentrating the fractions under reduced pressure (2.7kPa), 860 mg of 4-benzo[b]thiophen-2-yl-3-benzyloxy-1H-pyrazole areobtained in the form of a white solid. IR spectrum (KBr): 3173; 2950;1586; 1530; 1501; 1445; 1363; 1304; 1215; 1166; 1022; 818; 745; 736;727; 693 and 564 cm⁻¹.

The4-benzo[b]thiophen-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

2.4 g of 2-benzothienylboronic acid, 6.6 cm³ of a 2N aqueous potassiumcarbonate solution and 660 mg of tetrakis(triphenylphosphine)palladiumare added to a solution, under an argon atmosphere with stirring, of 2 gof 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm³ oftoluene to which 10 cm³ of ethanol have been added. After heating for 5h at the reflux of the solvent and for 16 h at a temperature in theregion of 20° C., the reaction medium is evaporated under reducedpressure (2.7 kPa). Ethyl acetate, water and carbon black are added tothe residue, which is filtered through supercel. The filtrate isseparated by settling out, and the organic phase is then washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The orange oil obtained (3.8 g) ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. Afterconcentrating the fractions under reduced pressure (2.7 kPa), theresulting cream solid is triturated in diisopropyl ether. Afterfiltration, 1.4 g of4-benzo[b]thiophen-2-yl-3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazoleare obtained in the form of a white solid. Mass spectrum (EI):460(+)=M(+); 305(+)=M(+)−Ts.

Exemple 82 1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-olhydrochloride

6 cm³ of 12N hydrochloric acid are added to a stirred solution of 640 mgof 1-[2-(3-benzyloxy-4-thiophen-3-ylpyrazol-1-yl)ethyl]piperidine in 10cm³ of ethanol. After 7 h at the reflux of the solvent, and then 15 h ata temperature in the region of 20° C., the reaction medium is evaporatedto dryness under reduced pressure (2.7 kPa). The residue is, threetimes, successively dissolved in ethanol and evaporated to dryness underreduced pressure (2.7 kPa), and it is then triturated in diisopropylether. The precipitate formed is filtered off and dried under vacuum(2.7 kPa), to give 470 mg of1-(2-piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-ol hydrochloridein the form of a white solid. Mass spectrum (CI): 278(+)=(M+H)(+);presence 36(+)/38(+)=HCl(+). ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: 1.40 (m, 1H); from 1.64 to 1.88 (m, 5H); 2.93 (m, 2H); from3.35 to 3.52 (m, 4H); 4.39 (t, J=6.5 Hz, 2H); 7.35 (dd, J=1.0 and 5.0Hz, 1H); 7.49 (dd, J=1.0 and 3.0 Hz, 1H); 7.55 (dd, J=3.0 and 5.0 Hz,1H); 7.94 (s, 1H); from 9.85 to 10.05 (very broad m, 1H); 10.4 (broad m,1H).

The 1-[2-(3-benzyloxy-4-thiophen-3-yl-pyrazol-1-yl)-ethyl]piperidine canbe prepared in the following way:

650 mg of 3-benzyloxy-4-thiophen-3-yl-1H-pyrazole are added,portionwise, to a suspension of 200 mg of sodium hydride (at 75% inliquid petroleum jelly) in 30 cm³ of dimethylformamide under an argonatmosphere and with stirring. After heating for 30 min at 50° C., themixture is stirred for 30 min at a temperature in the region of 20° C.,and 654 mg of 1-(2-chloroethyl)piperidine hydrochloride are then addedportionwise thereto. The reaction medium is stirred for 15 h at atemperature in the region of 20° C. and is then poured into 100 cm³ ofwater. The aqueous phase is extracted twice with ethyl acetate. Theorganic phases are combined, washed successively with two times waterand a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and evaporated under reduced pressure (2.7 kPa), togive an orange oil which is purified by flash chromatography on aluminaCTB1 under an argon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate(95/5 by volume)]. After concentrating the fractions under reducedpressure, 640 mg of1-[2-(3-benzyloxy-4-thiophen-3-yl-pyrazol-1-yl)ethyl]piperidine areobtained in the form of a yellow oil. ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.32 to 1.54 (m, 6H); 2.38 (m, 4H); 2.67 (t, J=6.5Hz, 2H); 4.06 (t, J=6.5 Hz, 2H); 5.30 (s, 2H); from 7.30 to 7.55 (m,8H); 7.98 (s, 1H).

The 3-benzyloxy-4-thiophen-3-yl-1H-pyrazole can be prepared in thefollowing way:

8.5 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 1.35 g of3-benzyloxy-4-thiophen-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm³of tetrahydrofuran. After heating for 15 h at the reflux of the solvent,the reaction medium is evaporated under reduced pressure (2.7 kPa) andethyl acetate is added to the residue. The organic phase is washedsuccessively with three times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The residue obtained (0.96 g) ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Afterconcentrating the fractions under reduced pressure (2.7 kPa), 650 mg of3-benzyloxy-4-thiophen-3-yl-1H-pyrazole are obtained in the form of acream solid.

Mass spectrum (EI): 256(+)=M(+); 91(+)=C₇H₇(+).

The 3-benzyloxy-4-thiophen-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazole canbe prepared in the following way:

1.7 g of 3-thienylboronic acid, 6.6 cm³ of a 2N aqueous potassiumcarbonate solution and 660 mg of tetrakis(triphenylphosphine)palladiumare added to a solution, under an argon atmosphere and with stirring, of2 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm³of toluene to which 10 cm³ of ethanol have been added. After heating for5 h at the reflux of the solvent and for 16 h at a temperature in theregion of 20° C., the reaction medium is evaporated under reducedpressure (2.7 kPa). Ethyl acetate, water and carbon black are added tothe residue, which is filtered through supercel. The filtrate isseparated by settling out, and the organic phase is then washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The resulting solid is triturated indiisopropyl ether, filtered and crystallized from 10 cm³ of ethanol.1.35 g of 3-benzyloxy-4-thiophen-3-yl-1-(toluene-4-sulfonyl)-1H-pyrazoleare thus obtained in the form of a beige solid. Mass spectrum (EI):410(+)=M(+); 255(+)=M(+)−Ts.

EXAMPLE 834-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidehydrochloride

4 cm³ of 3N hydrochloric diethyl ether are added to a solution of 442 mgof 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide in20 cm³ of ethanol. After stirring for 1 h at a temperature in the regionof 20° C., the solution is evaporated to dryness under reduced pressure(2.7 kPa). The residue is taken up with 25 cm³ of ethanol. The solutionobtained is introduced into an autoclave, and 52 mg ofpalladium-on-charcoal at 10% are added thereto, and it is then placedunder hydrogen (10 bar). After stirring for 8 h at 22° C., the reactionmedium is filtered through supercel, the filtrate is evaporated and theresidue is triturated in diisopropyl ether. The resulting solid isfiltered off, and dried under vacuum (2.7 kPa), to give 118 mg of4-[3-hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidehydrochloride in the form of a cream solid. Mass spectrum (CI):315(+)=(M+H)(+). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.41 (m,1H); from 1.64 to 1.89 (m, 5H); 2.94 (m, 2H); from 3.25 to 3.53 (m, 4H);4.41 (t, J=6.5 Hz, 2H); 7.23 (broad m, 1H); 7.73 (broad d, J=8.5 Hz,2H); from 7.83 to 7.91 (m, 3H); 8.14 (s, 1H); from 9.80 to 9.95 (verybroad m, 1H); 10.65 (broad s, 1H).

The 4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidecan be prepared in the following way:

527 mg of 4-(3-benzyloxy-1H-pyrazol-4-yl)benzamide are added,portionwise, to a suspension of 144 mg of sodium hydride (75% in liquidpetroleum jelly) in 30 cm³ of dimethylformamide under an atmosphere ofargon and with stirring. After heating at 50° C. for 30 min, the mixtureis stirred for 30 min at a temperature in the region of 20° C. and then465 mg of 1-(2-chloroethyl)piperidine hydrochloride are addedportionwise thereto. The reaction medium is stirred for 15 h at atemperature in the region of 20° C., and is then poured into 100 cm³ ofwater. The aqueous phase is extracted twice with ethyl acetate. Theorganic phases are combined, washed successively with two times waterand a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated under reduced pressure (2.7 kPa). Theresulting solid is triturated in diisopropyl ether, filtered andcrystallized from acetone. 445 mg of4-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide arethus obtained in the form of a white solid. ¹H NMR spectrum (300 MHz)-δin ppm-DMSO-d6: from 1.32 to 1.54 (m, 6H); 2.39 (m, 4H); 2.69 (t, J=6.5Hz, 2H); 4.09 (t, J=6.5 Hz, 2H); 5.33 (s, 2H); 7.24 (broad m, 1H); from7.32 to 7.46 (m, 3H); 7.52 (broad d, J=8.5 Hz, 2H); 7.70 (broad d, J=7.5Hz, 2H); from 7.81 to 7.88 (m, 3H); 8.17 (s, 1H).

The 4-(3-benzyloxy-1H-pyrazol-4-yl)benzamide can be prepared in thefollowing way:

6.5 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 1.1 g of4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]benzamide in 30cm³ of tetrahydrofuran. After heating for 15 h at the reflux of thesolvent, the reaction medium is cooled in an ice bath. After filtrationand then drying of the resulting crystals under vacuum (2.7 kPa), 527 mgof 4-(3-benzyloxy-1H-pyrazol-4-yl)benzamide are obtained in the form ofa white solid. IR spectrum (KBr): 3403; 3176; 1667; 1611; 1576; 1553;1517; 1485; 1393; 1379; 1226; 1040; 1027 and 739 cm⁻¹.

The 4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]benzamide canbe prepared in the following way:

2.72 g of 4-aminocarbonylphenylboronic acid, 8.3 cm³ of a 2N aqueouspotassium carbonate solution and 830 mg oftetrakis(triphenylphosphine)palladium are added to a solution, under anargon atmosphere and with stirring, of 2.5 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm³ oftoluene to which 10 cm³ of ethanol have been added. After heating for 15h at the reflux of the solvent, the reaction medium is cooled to atemperature in the region of 20° C. and evaporated under reducedpressure (2.7 kPa). Ethyl acetate, water and carbon black are added tothe residue, which is filtered through supercel. The filtrate isseparated by settling out, and the organic phase is then washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The yellow oil obtained (3.7 g) ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: cyclohexane/ethyl acetate (50/50 then 20/80 by volume)].After concentrating the fractions under reduced pressure (2.7 kPa), 1.1g of 4-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-benzamideare obtained in the form of a white solid.

Mass spectrum (EI): 447(+)=M(+); 91(+)=C₇H₇(+).

EXAMPLE 843-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidehydrochloride

4 cm³ of 3N hydrochloric diethyl ether are added to a solution of 690 mgof 3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide in20 cm³ of ethanol. After stirring for 45 min at a temperature in theregion of 20° C., the solution is evaporated to dryness under reducedpressure (2.7 kPa). The residue is taken up with 25 cm³ of ethanol. Thesolution obtained is introduced into an autoclave, and 80 mg ofpalladium-on-charcoal at 10% are added thereto, and it is then placedunder hydrogen (10 bar). After stirring for 8 h at 22° C., the reactionmedium is filtered through supercel, the filtrate is evaporated and theresidue is triturated in diisopropyl ether. The resulting solid isfiltered off, and dried under vacuum (2.7 kPa), to give 528 mg of3-[3-hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidehydrochloride in the form of a pale yellow solid. Mass spectrum (CI):315(+)=(M+H)(+).

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.40 (m, 1H); from 1.65to 1.88 (m, 5H); 2.94 (m, 2H); from 3.41 to 3.54 (m, 4H); 4.42 (t, J=6.5Hz, 2H); 7.33 (broad m, 1H); 7.42 (t, J=8.0 Hz, 1H); 7.64 (broad d,J=8.0 Hz, 1H); 7.82 (broad d, J=8.0 Hz, 1H); 7.94 (broad m, 1H); 8.10(s, 1H); 8.14 (broad s, 1H); from 9.90 to 10.05 (very broad m, 1H);10.55 (broad s, 1H).

The 3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamidecan be prepared in the following way:

1.16 g of 3-(3-benzyloxy-1H-pyrazol-4-yl)benzamide are added,portionwise, to a suspension of 315 mg of sodium hydride (75% in liquidpetroleum jelly) in 30 cm³ of dimethylformamide under an argonatmosphere and with stirring. After heating for 30 min at 50° C., themixture is stirred for 30 min at a temperature in the region of 20° C.,and 1 g of 1-(2-chloroethyl)piperidine hydrochloride is addedportionwise thereto. The reaction medium is stirred for 15 h at atemperature in the region of 20° C. and is then poured into 100 cm³ ofwater. The aqueous phase is extracted twice with ethyl acetate. Theorganic phases are combined, washed successively with two times waterand a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered, and evaporated under reduced pressure (2.7 kPa), togive a yellow oil (1.6 g) which is purified by flash chromatography onsilica under an argon pressure (50 kPa) [eluent: dichloromethane thendichloromethane/methanol (98/2, 95/5 then 90/10 by volume)]. Afterconcentrating the fractions under reduced pressure, 700 mg of3-[3-benzyloxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide areobtained in the form of a pale yellow oil. ¹H NMR spectrum (300 MHz)-δin ppm-in DMSO-d6: from 1.33 to 1.54 (m, 6H); 2.40 (m, 4H); 2.70 (t,J=6.5 Hz, 2H); 4.10 (t, J=6.5 Hz, 2H); 5.33 (s, 2H); from 7.30 to 7.44(m, 5H); 7.53 (broad d, J=8.5 Hz, 2H); 7.63 (broad d, J=8.0 Hz, 1H);7.80 (broad d, J=8.0 Hz, 1H); 7.92 (broad m, 1H); 8.11 (s, 1H); 8.15(broad s, 1H).

The 3-(3-benzyloxy-1H-pyrazol-4-yl)benzamide can be prepared in thefollowing way:

11.8 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran is added to a solution, under an argon atmosphere andwith stirring, of 2.1 g of3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]benzamide in 40cm³ of tetrahydrofuran. After heating for 15 h at the reflux of thesolvent, the reaction medium is evaporated under reduced pressure (2.7kPa) and ethyl acetate is added to the residue. The organic phase iswashed successively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The residue is triturated indiisopropyl ether, filtered and dried under vacuum (2.7 kPa), to give1.16 g of 3-(3-benzyloxy-1H-pyrazol-4-yl)benzamide in the form of acream solid. IR spectrum (KBr): 3332; 3196; 2975; 1682; 1606; 1581;1572; 1505; 1447; 1389; 1280; 1232; 1049; 732; 695; 672 and 637 cm⁻¹.

The 3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]benzamide canbe prepared in the following way:

2.72 g of 3-aminocarbonylphenylboronic acid, 8.3 cm³ of a 2N aqueouspotassium carbonate solution and 830 mg oftetrakis(triphenylphosphine)palladium are added to a solution, under anargon atmosphere and with stirring, of 2.5 g of3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm³ oftoluene to which 10 cm³ of ethanol have been added. After heating for 15h at the reflux of the solvent, the reaction medium is cooled in an icebath. After filtration and then drying of the resulting crystals undervacuum (2.7 kPa), 2.1 g of3-[3-benzyloxy-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-benzamide areobtained in the form of a white solid.

Mass spectrum (EI): 447(+)=M(+); 91(+)=C₇H₇(+).

EXAMPLE 85 (−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride

15 cm³ of 12N hydrochloric acid are added to a stirred solution of 1.44g of (+)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octanein 20 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue is,three times, successively dissolved in ethanol and evaporated to drynessunder reduced pressure (2.7 kPa), and is then triturated in 20 cm³ ofdiisopropyl ether. The precipitate formed is filtered off and driedunder vacuum (2.7 kPa), to give 1.2 g of(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride in the form of a white solid. Mass spectrum (EI):269(+)=M(+); presence 36(+)/38(+)=HCl(+). ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.69 to 2.04 (m, 4H); 2.43 (m, 1H); from 3.22 to3.47 (m, 4H); from 3.72 to 3.85 (m, 2H); 4.67 (m, 1H); 7.15 (tt, J=1.5and 7.5 Hz, 1H); 7.34 (broad t, J=7.5 Hz, 2H); 7.67 (broad d, J=7.5 Hz,2H); 8.18 (s, 1H); 10.2 (broad m, 1H); 10.4 (broad m, 1H). [α]²⁰_(D)=−17.4+/−0.6° (c 0.5, MeOH).

The (+)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octaneand the(−)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane canbe prepared in the following way: an ethanolic solution containing 1.5 gof 3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octane isintroduced onto a column, 6 cm in diameter, containing 800 g ofChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of 10% ethanol, 10% methanol, 0.1% triethylamine and80% heptane. The flow of the mobile phase is 90 ml/min. Thedextrorotatory enantiomer is eluted in the first position, the solutionis evaporated to dryness under reduced pressure (2.7 kPa), to give 0.66g of oil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.30 (m, 1H); from 1.50to 1.71 (m, 3H); 2.08 (m, 1H); from 2.65 to 2.79 (m, 3H); 2.99 (m, 1H);from 3.15 to 3.42 (m, 2H); 4.27 (m, 1H); 5.33 (s, 2H); 7.15 (tt, J=1.5and 7.5 Hz, 1H); from 7.30 to 7.44 (m, 5H); 7.51 (broad d, J=7.5 Hz,2H); 7.69 (broad d, J=7.5 Hz, 2H); 8.20 (s, 1H). [α]²⁰ _(D)=+27.0+/−0.8°(c 0.5, MeOH). The solution containing the levorotatory enantiomereluted in the second position is evaporated to dryness under reducedpressure (2.7 kPa), to give 0.65 g of oil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.31 (m, 1H); from 1.50to 1.72 (m, 3H); 2.09 (m, 1H); from 2.66 to 2.80 (m, 3H); 2.99 (m, 1H);from 3.16 to 3.43 (m, 2H); 4.29 (m, 1H); 5.34 (s, 2H); 7.14 (tt, J=1.5and 7.5 Hz, 1H); from 7.30 to 7.44 (m, 5H); 7.51 (broad d, J=7.5 Hz,2H); 7.70 (broad d, J=7.5 Hz, 2H); 8,20 (s, 1H). [α]²⁰ _(D)=−27.0+/−0.8°(c 0.5, MeOH).

EXAMPLE 86 (+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride

15 cm³ of 12N hydrochloric acid are added to a stirred solution of 1.44g of (−)-3-(3-benzyloxy-4-phenylpyrazol-1-yl)-1-azabicyclo[2.2.2]octanein 20 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue is,three times, successively dissolved in ethanol and evaporated to drynessunder reduced pressure (2.7 kPa), and is then triturated in 20 cm³ ofdiisopropyl ether. The precipitate formed is filtered off and driedunder vacuum (2.7 kPa), to give 1.2 g of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-olhydrochloride in the form of a beige solid. Mass spectrum (EI):269(+)=M(+); presence 36(+)/38(+)=HCl(+). ¹H NMR spectrum (300 MHz)-δ inppm-in DMSO-d6: from 1.70 to 2.03 (m, 4H); 2.43 (m, 1H); from 3.22 to3.47 (m, 4H); from 3.72 to 3.86 (m, 2H); 4.68 (m, 1H); 7.15 (tt, J=1.5and 7.5 Hz, 1H); 7.34 (broad t, J=7.5 Hz, 2H); 7.67 (broad d, J=7.5 Hz,2H); 8.19 (s, 1H); 10.2 (broad m, 1H); from 10.3 to 10.5 (very broad m,1H). [α]²⁰ _(D)=+13.7+/−0.6° (c 0.5, MeOH).

EXAMPLE 87(−)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-olhydrochloride

10 cm³ of 12N hydrochloric acid are added to a stirred solution of 825mg of(−)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanein 10 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue is,three times, successively dissolved in ethanol and evaporated to drynessunder reduced pressure (2.7 kPa), and it is then triturated indiisopropyl ether. The precipitate formed is filtered off and driedunder vacuum (2.7 kPa), to give 700 mg of(−)-1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-olhydrochloride in the form of a white solid. Mass spectrum (EI):283(+)=M(+). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.66 to1.93 (m, 4H); 2.05 (m, 1H); 2.52 (masked m, 1H); 2.94 (m, 1H); from 3.12to 3.40 (m, 5H); from 3.98 to 4.12 (m, 2H); 7.13 (tt, J=1.5 and 7.5 Hz,1H); 7.33 (broad t, J=7.5 Hz, 2H); 7.64 (broad d, J=7.5 Hz, 2H); 7.99(s, 1H); 10.1 (broad m, 1H). [α]²⁰ _(D)=−36.8+/−0.8° (c 0.5, MeOH)

The(−)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octaneand the(+)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

A solution of 5 g of 3-benzyloxy-4-phenylpyrazole in 30 cm³ ofdimethylformamide is added gradually, under an argon atmosphere and at atemperature in the region of 20° C., to a suspension of 1.9 g of sodiumhydride (75% by mass in liquid petroleum jelly) in 50 cm³ ofdimethylformamide. After stirring for 1 h at a temperature in the regionof 50° C., 5.8 g of 3-chloromethyl-1-azabicyclo[2.2.2]octanehydrochloride are added in small portions, and the mixture is thenheated for 15 hours at a temperature in the region of 90° C. The mixtureis cooled to a temperature in the region of 20° C. and is then pouredinto 400 cm³ of water. The aqueous phase is extracted with two timesethyl acetate. The combined organic phases are washed with two timeswater and brine, and then dried over magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure (2.7 kPa). The orange oilobtained is purified by flash chromatography on alumina CTB1 under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (10/90 byvolume), ethyl acetate and then ethyl acetate/methanol (95/5 byvolume)]. After concentrating the fractions under reduced pressure, 1.7g of a pale yellow oil are obtained. An ethanolic solution of this oilis introduced onto a column, 8 cm in diameter, containing 1180 g ofChiracel OD™ chiral stationary phase. The elution is carried out bymeans of a mixture of 50% ethanol, 0.1% triethylamine and 50% heptane.The flow rate of the mobile phase is 120 ml/min. The levorotatoryenantiomer is eluted in the first position, the solution is evaporatedto dryness under reduced pressure (2.7 kPa), to give 0.82 g of oil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.24 to 1.59 (m,4H); 1.78 (m, 1H); 2.14 (m, 1H); 2.37 (m, 1H); from 2.59 to 2.90 (m,5H); 3.89 (d, J=8.0 Hz, 2H); 5.31 (s, 2H); 7.14 (tt, J=1.5 and 7.5 Hz,1H); from 7.30 to 7.44 (m, 5H); 7.50 (broad d, J=8.5 Hz, 2H); 7.64(broad d, J=8.5 Hz, 2H); 8.09 (s, 1H). [α]²⁰ _(D)=−37.8+/−0.8° (c 0.5,MeOH). The solution containing the dextrorotatory enantiomer eluted inthe second position is evaporated to dryness under reduced pressure (2.7kPa), to give 0.74 g of oil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.24 to 1.60 (m,4H); 1.78 (m, 1H); 2.14 (m, 1H); 2.36 (m, 1H); from 2.60 to 2.90 (m,5H); 4.00 (d, J=8.0 Hz, 2H); 5.31 (s, 2H); 7.14 (tt, J=1.5 and 7.5 Hz,1H); from 7.30 to 7.44 (m, 5H); 7.50 (broad d, J=8.5 Hz, 2H); 7.64(broad d, J=8.5 Hz, 2H); 8.09 (s, 1H). [α]²⁰ _(D)=−39.1+/−0.9° (c 0.5,MeOH).

EXAMPLE 88(+)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-olhydrochloride

10 cm³ of 12N hydrochloric acid are added to a stirred solution of 740mg of(+)-3-(3-benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-aza-bicyclo[2.2.2]octanein 10 cm³ of ethanol. After 7 h at the reflux of the solvent, and then15 h at a temperature in the region of 20° C., the reaction medium isevaporated to dryness under reduced pressure (2.7 kPa). The residue is,three times, successively dissolved in ethanol and evaporated to drynessunder reduced pressure (2.7 kPa), and it is then triturated indiisopropyl ether. The precipitate formed is filtered off and driedunder vacuum (2.7 kPa), to give 600 mg of(+)-1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-olhydrochloride in the form of a white solid. Mass spectrum (EI):283(+)=M(+). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.67 to1.94 (m, 4H); 2.06 (m, 1H); 2.52 (masked m, 1H); 2.94 (m, 1H); from 3.12to 3.40 (m, 5H); from 3.99 to 4.12 (m, 2H); 7.13 (tt, J=1.5 and 7.5 Hz,1H); 7.33 (broad t, J=7.5 Hz, 2H); 7.64 (broad d, J=7.5 Hz, 2H); 7.99(s, 1H); 10.05 (broad m, 1H). [α]²⁰ _(D)=+36.5+/−0.8° (c 0.5, MeOH).

EXAMPLE 891-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride

10 cm³ of 12N hydrochloric acid are added to a stirred solution of 430mg of3-[3-benzyloxy-4-(4-chlorophenyl)-pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneboranein 10 cm³ of ethanol. After 15 h at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with water. The resulting solution is brought to a pH in theregion of 8 with 1N sodium hydroxide and extracted with ethyl acetate.The organic phase is dried over magenesium sulfate, filtered, andconcentrated to dryness under reduced pressure (2.7 kPa). The residualsolid is triturated in diisopropyl ether, filtered, and dried underreduced pressure (2.7 kPa), to give 137 mg of1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a white solid. Mass spectrum (EI): 317(+)/. . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum (400 MHz)-δ in ppm-inDMSO-d6: from 1.30 to 1.61 (m, 4H); 1.78 (m, 1H); 2.15 (m, 1H); 2.38 (m,1H); from 2.66 to 2.81 (m, 4H); 2.88 (m, 1H); 3.91 (d, J=8.0 Hz, 2H);7.37 (broad d, J=8.5 Hz, 2H); 7.67 (broad d, J.=8.5 Hz, 2H); 8.00 (s,1H); from 10.35 to 10.5 (very broad m, 1H).

The3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneboranecan be prepared in the following way:

A solution of 3 g of 3-benzyloxy-4-(4-chlorophenyl)-1H-pyrazole and of 3g of potassium tert-butoxide in 30 cm³ of dimethylformamide, under aninert atmosphere and with stirring, is heated for 30 min at 50° C., and3.1 g of 3-chloromethyl-1-azabicyclo[2.2.2]octane hydrochloride are thenadded thereto. After refluxing for 15 h, the reaction medium is pouredinto water, and the mixture is extracted with two times ethyl acetate.The organic phases are washed successively with two times water and asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and evaporated under reduced pressure (2.7 kPa). The beige oil(5.3 g) obtained is purified by flash chromatography on alumina CTB1under an argon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate(20/80 by volume), ethyl acetate then ethyl acetate/methanol (90/10 byvolume)]. After concentrating the fractions under reduced pressure (2.7kPa), a solid is obtained which is dissolved in 10 cm³ oftetrahydrofuran under an inert atmosphere. 3 cm³ of a 1N solution ofborane in tetrahydrofuran are added to the solution, which is beingstirred and has been cooled to −60° C. After reaction for 2 h 30 min at−60° C., 15 cm³ of water are added to the reaction medium, thetemperature of the mixture is allowed to rise to a temperature in theregion of 20° C. and the solution is extracted with ethyl acetate. Theorganic phase is washed with two times water and a saturated aqueoussodium chloride solution, dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa), to give an oil (1 g) which is purifiedby flash chromatography on alumina CTB1 under an argon pressure (50 kPa)[eluent: ethyl acetate, ethyl acetate/methanol (90/10 by volume) thendichloromethane/methanol (80/20 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), 430 mg of3-[3-benzyloxy-4-(4-chlorophenyl)-pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneboraneare obtained in the form of an oil which is used without any otherpurification for the remainder of the synthesis.

EXAMPLE 90(−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride

7 cm³ of 12N hydrochloric acid are added to a stirred solution of 690 mgof(+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 10 cm³ of ethanol. After-7 h at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andevaporated to dryness under reduced pressure (2.7 kPa). The residue istriturated in diisopropyl ether, filtered, and dried under reducedpressure (2.7 kPa), to give 580 mg of(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a beige solid. Mass spectrum (EI): 303(+)/. . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: from 1.68 to 2.03 (m, 4H); 2.42 (m, 1H); from 3.20 to 3.55 (m,4H); 3.78 (m, 2H); 4.66 (m, 1H); 4.71 (broad d, J=8.5 Hz, 2H); 7.71(broad d, J=8.5 Hz, 2H); 8.25 (s, 1H); 10.35 (broad m, 1H); 10.65 (broadm, 1H). [α]²⁰ _(D)=−19.4+/−0.7° (c 0.5, MeOH).

The(+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneand the(−)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

An ethanolic solution containing 0.29 g of(+/−)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octaneis introduced onto a column, 8 cm in diameter, containing 1180 g ofChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of heptane, of ethanol, of methanol and oftriethylamine (80/10/10/0.1 by volume), the flow rate of the mobilephase being 120 ml/min. The dextrorotatory enantiomer is eluted in thefirst position, the solution is evaporated to dryness under reducedpressure (2.7 kPa), so as to obtain 0.69 g of(+)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octanein the form of an oil.

Mass spectrum (EI): 393(+)/ . . . =M(+)/ . . . (1 Cl); 91(+)=C₇H₇. [α]²⁰_(D)=+25.4+/−0.8° (c 0.5, MeOH). The solution containing thelevorotatory enantiomer eluted in the second position is evaporated todryness under reduced pressure (2.7 kPa) so as to obtain 0.69 g of(−)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octanein the form of an oil.

Mass spectrum (EI): 393(+)/ . . . =M(+)/ . . . (1 Cl); 91(+)=C₇H₇(+).Optical rotation: [α]²⁰ _(D)=−26.2+/−0.8° (c 0.5, MeOH).

EXAMPLE 91(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride

7 cm³ of 12N hydrochloric acid are added to a stirred solution of 690 mgof(−)-3-[3-benzyloxy-4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 10 cm³ of ethanol. After 7 h at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andevaporated to dryness under reduced pressure (2.7 kPa). The residue istriturated in diisopropyl ether, filtered and dried under reducedpressure (2.7 kPa), to give 580 mg of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(4-chlorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a beige solid. Mass spectrum (EI): 303(+)/. . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: from 1.67 to 2.02 (m, 4H); 2.42 (m, 1H); from 3.22 to 3.50 (m,4H); 3.79 (m, 2H); 4.66 (m, 1H); 7.41 (broad d, J=8.5 Hz, 2H); 7.71(broad d, J=8.5 Hz, 2H); 8.25 (s, 1H); from 10.2 to 10.3 (very broad m,1H); 10.65 (broad m, 1H). [α]²⁰ _(D)=+17.7+/−0.6° (c 0.5, MeOH).

EXAMPLE 92(−)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-olhydrochloride

5 cm³ of 12N hydrochloric acid are added to a stirred solution of 135 mgof(+)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 5 cm³ of ethanol. After 7 h at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andevaporated to dryness under reduced pressure (2.7 kPa). The residue istriturated in diisopropyl ether, filtered and dried under reducedpressure (2.7 kPa), to give 91 mg of(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a white solid. Mass spectrum (EI):287(+)=M(+). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.66 to2.03 (m, 4H); 2.42 (m, 1H); from 3.20 to 3.49 (m, 4H); 3.79 (m, 2H);4.66 (m, 1H); 7.19 (broad t, J=9.0 Hz, 2H); 7.71 (broad dd, J=6.0 and9.0 Hz, 2H); 8.17 (s, 1H); 10.15 (broad m, 1H); 10.5 (s, 1H). [α]²⁰_(D)=−14.9+/−0.7° (c 0.5, MeOH).

The(+)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneand the(−)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

A solution of 2 g of 3-benzyloxy-4-(4-fluorophenyl)-1H-pyrazole and of 1g of potassium tert-butoxide in 20 cm³ of dimethylformamide, under aninert atmosphere, is stirred for 1 h 30 min at a temperature in theregion of 20° C., and then a solution of 2.3 g of toluene-4-sulfonicacid 1-azabicyclo[2.2.2]oct-3-yl ester in 25 cm³ of dimethylformamide isadded thereto. After heating for 15 h at 100° C., the reaction medium ispoured into water, and the mixture is extracted with two times ethylacetate. The combined organic phases are washed successively with twotimes water and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated under reduced pressure (2.7 kPa). Theorange oil obtained (2.3 g) is purified by flash chromatography onalumina CTB1 under an argon pressure (50 kPa) [eluent: ethyl acetatethen ethyl acetate/methanol (98/2 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), an orange oil is obtained(1.5 g), which is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: ethyl acetate/methanol (95/5 by volume)then dichloromethane/methanol (98/2, 95/5 then 90/10 by volume)].Concentrating the appropriate fractions under reduced pressure (2.7 kPa)gives an orange oil (500 mg) which is again purified by flashchromatography on alumina CTB1 under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (10/90 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), 290 mg of(R,S)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]-octaneare obtained in the form of a pale yellow oil. ¹H NMR spectrum (300MHz)-δ in ppm-in DMSO-d6: 1.28 (m, 1H); from 1.49 to 1.71 (m, 3H); 2.08(m, 1H); from 2.65 to 2.79 (m, 3H); 2.98 (m, 1H); from 3.14 to 3.44 (m,2H); 4.25 (m, 1H); 5.33 (m, 2H); 7.18 (broad t, J=9.0 Hz, 2H); from 7.30to 7.44 (m, 3H); 7.50 (broad d, J=7.5 Hz, 2H); 7.71 (broad dd, J=6.0 and9.0 Hz, 2H); 8.20 (s, 1H)

An ethanolic solution containing 0.29 g of(+/−)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo-[2.2.2]octaneis introduced onto a column, 8 cm in diameter, containing 1180 g ofChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of heptane, of ethanol, of methanol and oftriethylamine (80/10/10/0.1 by volume), the flow rate of the mobilephase being 120 ml/min. The dextrorotatory enantiomer is eluted in thefirst position, the solution is evaporated to dryness under reducedpressure (2.7 kPa) to give 0.135 g of(+)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]-octanein the form of an oil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.30 (m, 1H); from 1.50to 1.71 (m, 3H); 2.08 (m, 1H); from 2.64 to 2.80 (m, 3H); 2.99 (m, 1H);from 3.16 to 3.43 (m, 2H); 4.26 (m, 1H); 5.33 (m, 2H); 7.17 (broad t,J=9.0 Hz, 2H); from 7.30 to 7.44 (m, 3H); 7.50 (broad d, J=7.5 Hz, 2H);7.71 (broad dd, J=6.0 and 9.0 Hz, 2H); 8.20 (s, 1H). [α]²⁰_(D)=+21.5+/−0.5° (c 0.5, MeOH). The solution containing thelevorotatory enantiomer eluted in the second position is evaporated todryness under reduced pressure (2.7 kPa), so as to obtain 0.137 g of(−)-3-[3-benzyloxy-4-(4-fluorophenyl)-pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneoil.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: 1.30 (m, 1H); from 1.49to 1.71 (m, 3H); 2.08 (m, 1H); from 2.65 to 2.80 (m, 3H); 2.98 (m, 1H);from 3.15 to 3.42 (m, 2H); 4.25 (m, 1H); 5.33 (m, 2H); 7.18 (broad t,J=9.0 Hz, 2H); from 7.30 to 7.44 (m, 3H); 7.50 (broad d, J=7.5 Hz, 2H);7.71 (broad dd, J=6.0 and 9.0 Hz, 2H); 8.20 (s, 1H). [α]²⁰_(D)=−20.2+/−0.6° (c 0.5, MeOH).

The 3-benzyloxy-4-(4-fluorophenyl)-1H-pyrazole can be prepared in thefollowing way:

20 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 3.5 g of3-benzyloxy-4-(4-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 50cm³ of tetrahydrofuran. After heating for 15 h at the reflux of thesolvent, the reaction medium is evaporated under reduced pressure (2.7kPa) and ethyl acetate is added to the residue. The organic phase iswashed successively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The yellow solid obtained (2.3 g) ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. Afterconcentrating the fractions under reduced pressure (2.7 kPa), 2 g of3-benzyloxy-4-(4-fluorophenyl)-1H-pyrazole are obtained in the form of awhite solid. Mass spectrum (EI): 268(+)=M(+).

The 3-benzyloxy-4-(4-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazolecan be prepared in the following way:

4.5 g of 4-fluorophenylboronic acid, 15 cm³ of a 2N aqueous potassiumcarbonate solution and 1.6 g of tetrakis(triphenylphosphine)palladiumare added to a solution, under an argon atmosphere and with stirring, of4.8 g of 3-benzyloxy-4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 40 cm³of toluene to which 10 cm³ of ethanol have been added. After heating for5 h at 100° C. and for 16 h at a temperature in the region of 20° C.,the reaction medium is evaporated under reduced pressure (2.7 kPa).Ethyl acetate, water and carbon black are added to the residue, which isfiltered through supercel. The filtrate is separated by settling out,and the organic phase is then washed successively with three times waterand a saturated aqueous sodium chloride solution; it is dried overmagnesium sulfate and evaporated under reduced pressure (2.7 kPa). Theyellow solid obtained (9 g) is purified by flash chromatography onsilica under an argon pressure (50 kPa) [eluent: cyclohexane/ethylacetate (95/5 by volume)]. After concentrating the fractions underreduced pressure (2.7 kPa), 3.5 g of3-benzyloxy-4-(4-fluorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole areobtained in the form of a yellow solid. Mass spectrum (EI): 422(+)=M(+);267(+)=422(+)−Ts; 91(+)=C₇H₇(+).

EXAMPLE 93(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-olhydrochloride

5 cm³ of 12N hydrochloric acid are added to a stirred solution of 137 mgof(−)-3-[3-benzyloxy-4-(4-fluorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 5 cm³ of ethanol. After 7 h at the reflux of the solvent, thereaction medium is cooled to a temperature in the region of 20° C. andevaporated to dryness under reduced pressure (2.7 kPa). The residue istriturated in diisopropyl ether, filtered, and dried under reducedpressure (2.7 kPa), to give 99 mg of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(4-fluorophenyl)-1H-pyrazol-3-olhydrochloride in the form of a white solid. Mass spectrum (EI):287(+)=M(+). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.69 to2.03 (m, 4H); 2.41 (m, 1H); from 3.19 to 3.50 (m, 4H); 3.79 (m, 2H);4.65 (m, 1H); 7.19 (broad t, J=9.0 Hz, 2H); 7.71 (broad dd, J=6.0 and9.0 Hz, 2H); 8.17 (s, 1H); from 10.1 to 10.3 (very broad m, 1H); 10.5(s, 1H). [α]²⁰ _(D)=+15.3+/−0.6° (c 0.5, MeOH).

EXAMPLE 94 3-[4-(4-Chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]-octanehydrochloride

A solution of 600 mg of 4-(4-chlorophenyl)-1H-pyrazole and of 420 mg ofpotassium tert-butoxide in 20 cm³ of dimethylformamide, in an inertatmosphere, is stirred for 2 h at a temperature in the region of 20° C.,and then a solution of 1.1 g of toluene-4-sulfonic acid1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm³ of dimethylformamide isadded thereto. After heating for 15 h at 100° C., reaction medium ispoured into water, and the mixture is extracted with two times ethylacetate. The combined organic phases are washed successively with twotimes water and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and evaporated under reduced pressure (2.7 kPa). Theorange oil obtained (1 g) is purified by flash chromatography on aluminaCTB1 under an argon pressure (50 kPa) [eluent: ethyl acetate then ethylacetate/methanol (95/5 by volume)]. After concentrating the fractionsunder reduced pressure (2.7 kPa), an orange oil is obtained (840 mg)which is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: ethyl acetate, ethyl acetate/methanol (80/20by volume) then dichloromethane/methanol (80/20 by volume)].Concentrating the appropriate fractions under reduced pressure (2.7 kPa)gives a cream solid (250 mg) which is dissolved in ethyl acetate. 0.85cm³ of 1N hydrochloric ether is added to the solution, which is thenevaporated to dryness under reduced pressure (2.7 kPa). The residue istriturated in diisopropyl ether and the resulting solid is filtered andthen dried under reduced pressure (2.7 kPa), to give 239 mg of3-[4-(4-chlorophenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanehydrochloride in the form of a cream solid. Mass spectrum (EI): 287(+)/. . . =M(+)/ . . . (1 Cl); 36(+)/38(+)=HCl(+)=salification via HCl. ¹HNMR spectrum (400 MHz)-δ in ppm-in DMSO-d6: 1.71 (m, 2H); 1.98 (m, 2H);2.41 (m, 1H); from 3.20 to 3.46 (m, 4H); 3.78 (m, 1H); 3.92 (m, 1H);4.89 (m, 1H); 7.44 (broad d, J=8.5 Hz, 2H); 7.64 (broad d, J=8.5 Hz,2H); 8.05 (s, 1H); 8.46 (s, 1H); from 10.05 to 10.35 (very broad m, 1H).

The 4-(4-chlorophenyl)-1H-pyrazole can be prepared in the following way:

21 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 2.8 g of4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 30 cm³ oftetrahydrofuran. After heating for 8 h at the reflux of the solvent, thereaction medium is evaporated under reduced pressure (2.7 kPa) and ethylacetate is added to the residue. The organic phase is washedsuccessively with two times water and a saturated aqueous sodiumchloride solution; it is dried over magnesium sulfate and evaporatedunder reduced pressure (2.7 kPa). The yellow solid obtained (2.1 g) ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: cyclohexane/ethyl acetate (50/50 by volume)]. Afterconcentrating the fractions under reduced pressure (2.7 kPa), 1.2 g of4-(4-chlorophenyl)-1H-pyrazole are obtained in the form of a whitesolid. Mass spectrum (EI): m/z=178 (M^(+.)) base peak, m/z=151[(M−HCN)^(+.)], m/z=116 [(m/z=151-Cl)⁺], m/z=89 [(m/z=116−HCN)⁺].

The 4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole can beprepared in the following way:

6.1 g of 4-chlorophenylboronic acid, 20 cm³ of a 2N aqueous potassiumcarbonate solution and 2.1 g of tetrakis(triphenylphosphine)palladiumare added to a solution, under an argon atmosphere and with stirring, of5 g of 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 60 cm³ of toluene towhich 15 cm³ of ethanol have been added. After heating for 3 h at 100°C. and for 16 h at a temperature in the region of 20° C., the reactionmedium is evaporated under reduced pressure (2.7 kPa). Ethyl acetate,water and carbon black are added to the residue, which is filteredthrough supercel. The filtrate is separated by settling out, and theorganic phase is then washed successively with two times water and asaturated aqueous sodium chloride solution; it is dried over magnesiumsulfate and evaporated under reduced pressure (2.7 kPa). The oilobtained (10.7 g) is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 byvolume)]. After concentrating the fractions under reduced pressure (2.7kPa), the resulting solid is triturated in diisopropyl ether. Afterfiltration and drying under reduced pressure (2.7 kPa), 2.8 g of4-(4-chlorophenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole are obtained inthe form of an orange solid. ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: 2.41 (s, 3H); from 7.44 to 7.53 (m, 4H); 7.80 (broad d, J=9.0Hz, 2H); 7.92 (broad d, J=9.0 Hz, 2H); 8.42 (s, 1H); 9.04 (s, 1H).

EXAMPLE 953-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo-[2.2.2]octanehydrochloride

A solution of 640 mg of 4-(4-chlorophenyl)-1H-pyrazole in 25 cm³ ofdimethylformamide is added gradually, under an argon atmosphere and at atemperature in the region of 20° C., to a suspension of 345 mg of sodiumhydride (at 75% by mass in liquid petroleum jelly) in 15 cm³ ofdimethylformamide. After stirring for 45 min at a temperature in theregion of 50° C., 1.4 g of 3-chloromethyl-1-azabicyclo[2.2.2]octanehydrochloride are added, in small portions, and the mixture is thenheated for 15 hours at a temperature in the region of 100° C. Themixture is cooled to a temperature in the region of 20° C. and is thenpoured into water. The aqueous phase is extracted with two times ethylacetate. The combined organic phases are washed with two times water andbrine, and are then dried over magnesium sulfate, filtered, andconcentrated to dryness under reduced pressure (2.7 kPa). The orange oilobtained (1.3 g) is purified by flash chromatography on alumina CTB1under an argon pressure (50 kPa) [eluent: ethyl acetate then ethylacetate/methanol (99/1 then 97/3 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), an oil is obtained (520 mg)which is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: dichloromethane/7N ammoniacal methanol (97/3by volume)]. Concentrating the appropriate fractions under reducedpressure (2.7 kPa) gives a pale yellow oil (330 mg) which is dissolvedin ethyl acetate. 0.985 cm³ of 1N hydrochloric ether is added to thesolution, which is then evaporated to dryness under reduced pressure(2.7 kPa). The residue is triturated in diisopropyl ether and theresulting solid is filtered and then dried under reduced pressure (2.7kPa), to give 353 mg of3-[4-(4-chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]-octanehydrochloride in the form of a white solid. Mass spectrum (EI): 301(+)/. . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum (300 MHz)-δ in ppm-inDMSO-d6: from 1.65 to 2.13 (m, 5H); 2.58 (m, 1H); 2.93 (m, 1H); from3.09 to 3.63 (m, 5H); from 4.22 to 4.34 (m, 2H); 7.42 (broad d, J=9.0Hz, 2H); 7.62 (broad d, J=9.0 Hz, 2H); 7.95 (s, 1H); 8.28 (s, 1H); from9.90 to 10.2 (very broad m, 1H).

EXAMPLE 963-[4-(3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane

A solution of 1.1 g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole in 25cm³ of dimethylformamide is added gradually, under an argon atmosphereand at a temperature in the region of 20° C., to a suspension of 530 mgof sodium hydride (at 75% by mass in liquid petroleum jelly) in 15 cm³of dimethylformamide. After stirring for 1 h at a temperature in theregion of 50° C., 2.07 g of 3-chloromethyl-1-azabicyclo[2.2.2]octanehydrochloride are added in small portions, and the mixture is thenheated for 15 hours at a temperature in the region of 100° C. Themixture is cooled to a temperature in the region of 20° C. and is thenpoured into water. The aqueous phase is extracted with two times ethylacetate. The combined organic phases are washed with two times water andbrine, and then dried over magnesium sulfate, filtered, and concentratedto dryness under reduced pressure (2.7 kPa). The orange oil obtained(1.8 g) is purified by flash chromatography on alumina CTB1 under anargon pressure (50 kPa) [eluent: ethyl acetate then ethylacetate/methanol (98/2 then 95/5 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), an oil is obtained (550 mg)which is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: dichloromethane/7N ammoniacal methanol (98/2by volume)]. Concentrating the appropriate fractions under reducedpressure (2.7 kPa) gives a pale yellow oil (400 mg) which is againpurified by flash chromatography on alumina CTB1 under an argon pressure(50 kPa) [eluent: ethyl acetate/methanol (95/5 by volume) thendichloromethane/methanol (80/20 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), 140 mg of3-[4-(3-chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octaneare obtained in the form of a white solid. Mass spectrum (CI): 332(+)/ .. . =(M+H)(+)/ . . . (1 Cl); 349(+)=(M+NH₄) (+)/ . . . . ¹H NMR spectrum(400 MHz)-δ in ppm-in DMSO-d6: from 1.28 to 1.57 (m, 4H); 1.77 (m, 1H);2.15 (m, 1H); 2.36 (m, 1H); from 2.58 to 2.88 (m, 5H); 3.85 (s, 3H);4.10 (d, J=8.0 Hz, 2H); 7.12 (d, J=8.0 Hz, 1H); 7.50 (dd, J=2.0 and 8.0Hz, 1H); 7.64 (d, J=2.0 Hz, 1H); 7.85 (s, 1H); 8.08 (s, 1H).

The 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole can be prepared in thefollowing way:

35 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 5.2 g of4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in 50cm³ of tetrahydrofuran. After heating for 6 h at the reflux of thesolvent, the reaction medium is evaporated under reduced pressure (2.7kPa) and ethyl acetate is added to the residue. The organic phase iswashed successively with two times water and the saturated aqueoussodium chloride solution; it is dried over magnesium sulfate andevaporated under reduced pressure (2.7 kPa). The orange solid obtained(5.1 g) is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: cyclohexane/ethyl acetate (50/50 by volume)].After concentrating the fractions under reduced pressure (2.7 kPa), 1.84g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole are obtained in the formof a pale yellow solid. Mass spectrum (EI): 208(+)/ . . . =M(+)/ . . .(1 Cl); 193(+)/ . . . =M(+)/ . . . −CH₃.

The 4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole canbe prepared in the following way:

9 g of 4-chloro-3-methoxyphenylboronic acid, 24 cm³ of a 2N aqueouspotassium carbonate solution and 2.45 g oftetrakis(triphenylphosphine)palladium are added to a solution, under anargon atmosphere and with stirring, of 5.6 g of4-iodo-1-(toluene-4-sulfonyl)-1H-pyrazole in 60 cm³ of toluene to which15 cm³ of ethanol have been added. After heating for 3 h at 100° C. andfor 16 h at a temperature in the region of 20° C., the reaction mediumis evaporated under reduced pressure (2.7 kPa). Ethyl acetate, water andcarbon black are added to the residue, which is filtered throughsupercel. The filtrate is separated by settling out, and the organicphase is then washed successively with two times water and a saturatedaqueous sodium chloride solution; it is dried over magnesium sulfate andevaporated under reduced pressure (2.7 kPa). The solid obtained istriturated in ethyl acetate, filtered and dried under reduced pressure(2.7 kPa), to give 5.2 g of4-(3-chloro-4-methoxyphenyl)-1-(toluene-4-sulfonyl)-1H-pyrazole in theform of a beige solid that is used without any other purification in thesubsequent step.

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6 for 70% of the mixture:2.40 (m, 3H); 3.88 (broad s, 3H); 7.19 (d, J=8.5 Hz, 1H); 7.50 (broad d,J=8.5 Hz, 2H); 7.71 (dd, J=2.0 and 8.5 Hz, 1H); from 7.88 to 7.93 (m,3H); 8.41 (s, 1H); 8.99 (s, 1H) (purity evaluated at 70% by ¹HNMR+starting boronic acid).

EXAMPLE 974-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-2-chlorophenoldihydrochloride

A solution, under an argon atmosphere and with stirring, of 470 mg of3-[4-(3-chloro-4-methoxyphenyl)-pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octanein 20 cm³ of dichloromethane is cooled in an ice-cold bath and 12 cm³ ofa 1N solution of boron tribromide in dichloromethane are then addedthereto. After having allowed the reaction medium to return to atemperature in the region of 20° C., the reaction is continued for 15 hat this temperature and then the mixture is poured into water to whichdichloromethane has been added. The solution is brought to a pH in theregion of 8 by adding 1N sodium hydroxide. The precipitate formed isfiltered off, and taken up in ethanol under hot conditions. Afterfiltration of the suspension under hot conditions, water and carbonblack are added to the filtrate, which is filtered through Wattman®paper and evaporated to dryness under reduced pressure (2.7 kPa). Theresulting beige solid (330 mg) is dissolved in 10 cm³ of ethanol and 10cm³ of 12N hydrochloric acid. After heating for 12 h at the reflux ofthe solvent, the mixture is cooled to a temperature in the region of 20°C., and evaporated to dryness under reduced pressure (2.7 kPa). Thesolid obtained is, three times, successively dissolved in ethanol andevaporated to dryness under reduced pressure (2.7 kPa), and is thentriturated in diisopropyl ether, filtered and dried under vacuum (2.7kPa), to give 370 mg of4-[1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-2-chlorophenoldihydrochloride in the form of a cream solid. Mass spectrum (ESP):318(+)/ . . . =(M+H)(+).

¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6: from 1.66 to 1.92 (m,4H); 2.07 (m, 1H); 2.60 (m, 1H); 2.94 (m, 1H); from 3.10 to 3.39 (m,5H); from 4.15 to 4.32 (m, 2H); 7.00 (d, J=8.5 Hz, 1H); 7.34 (dd, J=2.5and 8.5 Hz, 1H); 7.56 (d, J=2.5 Hz, 1H); 7.85 (s, 1H); 8.16 (s, 1H);from 9.80 to 10.3 (very broad m, 2H).

EXAMPLE 984-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol

A solution, under an argon atmosphere and with stirring, of 750 mg of3-[4-(3-chloro-4-methoxyphenyl)-pyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 25 cm³ of dichloromethane is cooled in an ice-cold bath and 11 cm³ ofa 1N solution of boron tribromide in dichloromethane are then addedthereto. After reaction for 30 min at a temperature in the region of 0°C., and heating for 3 h at 40° C. then for 15 h at a temperature in theregion of 20° C., the reaction mixture is poured into water to whichdichloromethane has been added. The resulting suspension is filtered andthe solid is taken up in water. The mixture is adjusted to pH 8 and thenextracted with ethyl acetate. The organic phase is washed successivelywith two times water and a saturated aqueous sodium chloride solution,dried over magnesium sulfate, and evaporated under reduced pressure (2.7kPa). The beige solid obtained (800 mg) is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent:dichloromethane/methanol (80/20 by volume)]. Concentrating theappropriate fractions under reduced pressure (2.7 kPa) gives a residuewhich is triturated in diisopropyl ether, filtered and dried underreduced pressure (2.7 kPa), to give 240 mg of4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol inthe form of a white solid. Mass spectrum (EI): 303(+)/ . . . =M(+)/ . .. (1 Cl). ¹H NMR spectrum (400 MHz)-δ in ppm-in DMSO-d6: 1.32 (m, 1H);1.54 (m, 1H); 1.70 (m, 2H); 2.02 (m, 1H); 2.77 (m, 3H); 2.98 (m, 1H);from 3.20 to 3.50 (m, 2H); 4.42 (m, 1H); 6.98 (d, J=9.0 Hz, 1H); 7.40(dd, J=2.0 and 9.0 Hz, 1H); 7.62 (d, J=2.0 Hz, 1H); 7.87 (s, 1H); 8.28(s, 1H); 10.05 (broad m, 1H).

The3-[4-(3-chloro-4-methoxyphenyl)pyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

A solution of 1.35 g of 4-(3-chloro-4-methoxyphenyl)-1H-pyrazole and of800 mg of potassium tert-butoxide in 20 cm³ of dimethylformamide, underan inert atmosphere, is stirred for 1 h at a temperature in the regionof 20° C. and a solution of 2 g of toluene-4-sulfonic acid1-azabicyclo[2.2.2]oct-3-yl ester in 20 cm³ of dimethylformamide is thenadded thereto. After heating for 18 h at 100° C., the reaction medium ispoured into water, and the mixture is extracted with two times ethylacetate. The combined organic phases are washed successively with twotimes water and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and evaporated under reduced pressure (2.7 kPa). Theorange oil obtained (2 g) is purified by flash chromatography on silicaunder an argon pressure (50 kPa) [eluent: ethyl acetate, ethylacetate/methanol (80/20 by volume) then dichloromethane/methanol (80/20by volume)]. After concentrating the fractions under reduced pressure(2.7 kPa), 480 mg of3-[4-(3-chloro-4-methoxyphenyl)-pyrazol-1-yl]-1-azabicyclo[2.2.2]octaneare obtained in the form of an orange oil. Mass spectrum (EI): m/z=317(M^(+.)), m/z=234 [(M-C₅H₉N)^(+.)], m/z=109 [C₇H₁₁N^(+.)], m/z=97[C₆H₁₁N^(+.)] base peak.

EXAMPLES 99 AND 100(−)-4-[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenoland(+)-4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol

An ethanolic solution containing 0.173 g of4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenol isintroduced onto a column, 8 cm in diameter, containing 1180 g ofChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of heptane, of ethanol, of methanol and oftriethylamine (80/10/10/0.1 by volume), the flow rate of the mobilephase being 120 ml/min. The levorotatory enantiomer is eluted in thefirst position, the solution is evaporated to dryness under reducedpressure (2.7 kPa), to give 0.093 g of(−)-4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenolin the form of an oil.

Mass spectrum (EI): 303(+)/ . . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum(400 MHz)-δ in ppm-in DMSO-d6: 1.31 (m, 1H); 1.53 (m, 1H); 1.68 (m, 2H);2.09 (m, 1H); from 2.67 to 2.80 (m, 3H); 2.97 (m, 1H); from 3.18 to 3.48(m, 2H); 4.39 (m, 1H); 6.95 (d, J=8.5 Hz, 1H); 7.38 (dd, J=2.5 and 8.5Hz, 1H); 7.60 (d, J=2.5 Hz, 1H); 7.85 (s, 1H); 8.23 (s, 1H); from 9.98to 10.15 (very broad m, 1H). [α]²⁰ _(D)=−4.1+/−0.6° (c 0.5, MeOH).

The solution containing the dextrorotatory enantiomer eluted in thesecond position is evaporated to dryness under reduced pressure (2.7kPa), to give 0.102 g of(+)-4-[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]-2-chlorophenolin the form of an oil.

Mass spectrum (EI): 303(+)/ . . . =M(+)/ . . . (1 Cl). ¹H NMR spectrum(400 MHz)-δ in ppm-in DMSO-d6: 1.35 (m, 1H); 1.54 (m, 1H); 1.70 (m, 2H);2.12 (m, 1H); from 2.70 to 2.83 (m, 3H); 3.00 (m, 1H); from 3.21 to 3.51(m, 2H); 4.43 (m, 1H); 6.95 (d, J=8.5 Hz, 1H); 7.38 (dd, J=2.5 and 8.5Hz, 1H); 7.61 (d, J=2.5 Hz, 1H); 7.87 (s, 1H); 8.27 (s, 1H); 10.05(broad m, 1H). [α]²⁰ _(D)=+5.3+/−0.4° (c 0.5, MeOH).

EXAMPLES 101 AND 102(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol and(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol

An ethanolic solution containing 0.3 g of(+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol isintroduced onto a column, 8 cm in diameter, containing 1180 g of 20 μMChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of heptane, of ethanol, of methanol and oftriethylamine (70/15/15/0.2 by volume), the flow rate of the mobilephase being 120 ml/min. The levorotatory enantiomer is eluted in thefirst position, the solution is evaporated to dryness under reducedpressure (2.7 kPa), to give 0.109 g of(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol inthe form of an oil.

Mass spectrum (EI): m/z=270 (M^(+.)), m/z=187 [(M-C₅H₉N)⁺] base peak. ¹HNMR spectrum (400 MHz)-δ in ppm-in DMSO-d6 (referenced at 2.50 ppm):1.31 (m, 1H); from 1.55 to 1.70 (m, 3H); 2.07 (m, 1H); from 2.65 to 2.75(m, 2H); 2.90 (m, 1H); from 3.14 to 3.39 (partially masked m, 3H); 4.21(m, 1H); 7.14 (m, 1H); 7.72 (broad d, J=7.5 Hz, 1H); 7.78 (m, 1H); 8.26(s, 1H); 8.45 (broad d, J=5.0 Hz, 1H); from 10.9 to 11.1 (broad m, 1H).[α]²⁰ _(D) =−40.7+/−0.8° (c 0.5, dimethylformamide).

The solution containing the dextrorotatory enantiomer eluted in thesecond position is evaporated to dryness under reduced pressure (2.7kPa), to give 0.113 g of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-ol inthe form of an oil.

Mass spectrum (EI): m/z=270 (M^(+.)), m/z=187 [(M-C₅H₉N)⁺] base peak. ¹HNMR spectrum (400 MHz)-δ in ppm-in DMSO-d6 (referenced at 2.50 ppm):1.32 (m, 1H); from 1.56 to 1.68 (m, 3H); 2.08 (m, 1H); from 2.66 to 2.76(m, 2H); 2.92 (m, 1H); from 3.14 to 3.42 (partially masked m, 3H); 4.22(m, 1H); 7.14 (m, 1H); 7.71 (broad d, J=7.5 Hz, 1H); 7.78 (m, 1H); 8.27(s, 1H); 8.47 (broad d, J=5.0 Hz, 1H); from 10.8 to 11.15 (broad m, 1H).[α]²⁰ _(D)=+35.4+/−0.8° (c 0.5, dimethylformamide).

The (+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-olhydrochloride can be prepared in the following way:

7 cm³ of 4N hydrochloric dioxane are added to a solution of 330 mg of3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-ylpyrazol-1-yl]-1-azabicyclo[2.2.2]octanein 7 cm³ of dioxane. After stirring for 15 h at a temperature in theregion of 20° C., the insoluble material formed is filtered off, rinsedwith diisopropyl ether and dried under reduced pressure (2.7 kPa), togive 300 mg of(+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-pyridin-2-yl-1H-pyrazol-3-olhydrochloride in the form of a white solid. Mass spectrum (EI): m/z=270(M^(+.)), m/z=187 [(M-C₅H₉N)⁺] base peak, m/z=36 (HCl^(+.)).

The3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-ylpyrazol-1-yl]-1-azabicyclo[2.2.2]octanecan be prepared in the following way:

A solution of 2.5 g of2-[3-(cyclohex-2-enyloxy)-1H-pyrazol-4-yl]pyridine and of 1.4 g ofpotassium tert-butoxide in 20 cm³ of dimethylformamide, under an inertatmosphere, is stirred for 1 h at 50° C. and a solution of 4 g oftoluene-4-sulfonic acid 1-azabicyclo[2.2.2]-oct-3-yl ester in 20 cm³ ofdimethylformamide is then added thereto. After heating for 15 h at 100°C., the reaction medium is poured into water, and the mixture isextracted with two times ethyl acetate. The combined organic phases arewashed successively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and evaporated underreduced pressure (2.7 kPa). The orange oil obtained (5.3 g) is purifiedby flash chromatography on alumina CTB1 under an argon pressure (50 kPa)[eluent: cyclohexane/ethyl acetate (60/40 by volume), ethyl acetate thenethyl acetate/methanol (95/5 by volume)]. After concentrating thefractions under reduced pressure (2.7 kPa), an oil is obtained which ispurified by flash chromatography on silica under an argon pressure (50kPa) [eluent: dichloromethane/methanol (95/5 then 70/30 by volume)].Concentrating the appropriate fractions under reduced pressure (2.7 kPa)gives 370 mg of3-[3-(cyclohex-2-enyloxy)-4-pyridin-2-ylpyrazol-1-yl]-1-azabicyclo[2.2.2]octanein the form of a pale yellow oil. ¹H NMR spectrum (400 MHz)-δ in ppm-inDMSO-d6 (referenced at 2.50 ppm): 1.35. (m, 1H); from 1.59 to 1.70 (m,4H); 1.78 (m, 1H); from 1.86 to 2.17 (m, 5H); from 2.67 to 2.78 (m, 3H);2.96 (m, 1H); 3.19 (m, 1H); from 3.27 to 3.37 (masked m, 1H); 4.30 (m,1H); 5.20 (m, 1H); from 5.95 to 6.04 (m, 2H); 7.10 (m, 1H); 7.74 (m,2H); 8.18 (s, 1H); 8.47 (broad d, J=5.0 Hz, 1H).

EXAMPLES 103 AND 104(+)-1-(1-Azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine and(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine

An ethanolic solution containing 0.13 g of(+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine isintroduced onto a column, 8 cm in diameter, containing 1180 g of 20 μMChiralpak AD™ chiral stationary phase. The elution is carried out bymeans of a mixture of heptane, of ethanol and of triethylamine(50/50/0.1 by volume), the flow rate of the mobile phase being 120ml/min. The levorotatory enantiomer is eluted in the first position, thesolution is evaporated to dryness under reduced pressure (2.7 kPa), togive 0.035 g of(−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine in theform of an oil.

Mass spectrum (EI): m/z=268 (M^(+.)) base peak, m/z=185 [(M-C₅H₉N)⁺],m/z=109 (C₇H₁₁N^(+.)). ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6(referenced at 2.50 ppm): 1.37 (m, 1H); from 1.61 to 1.74 (m, 3H); 2.11(m, 1H); from 2.71 to 2.85 (m, 3H); 3.00 (m, 1H); from 3.12 to 3.53(partially masked m, 2H); 4.21 (m, 1H); 4.65 (broad m, 2H); 7.13 (tt,J=1.5 and 7.5 Hz, 1H); 7.32 (broad t, J=7.5 Hz, 2H); 7.52 (broad d,J=7.5 Hz, 2H); 7.90 (s, 1H). [α]²⁰ _(D)=−(dimethylformamide).

The solution containing the dextrorotatory enantiomer eluted in thesecond position is evaporated under reduced pressure (2.7 kPa), to give0.039 g of(+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine in theform of an oil.

Mass spectrum (EI): m/z=268 (M^(+.)), m/z=185 [(M-C₅H₉N)⁺], m/z=109(C₇H₁₁N^(+.)) base peak. ¹H NMR spectrum (300 MHz)—δ in ppm-in DMSO-d6(referenced at 2.50 ppm): 1.34 (m, 1H); from 1.60 to 1.73 (m, 3H); 2.09(m, 1H); from 2.68 to 2.82 (m, 3H); from 2.90 to 3.53 (partially maskedm, 3H); 4.19 (m, 1H); 4.63 (broad m, 2H); 7.12 (broad t, J=7.5 Hz, 1H);7.32 (broad t, J=7.5 Hz, 2H); 7.51 (broad d, J=7.5 Hz, 2H); 7.89 (s,1H). [α]²⁰ _(D)=+(dimethylformamide).

The (+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylaminecan be prepared in the following way:

1.1 g of 1,3-dimethylbarbituric acid and 50 mg oftetrakis(triphenylphosphine)palladium are added to a solution of 280 mgofdiallyl-[1-(1-azabicyclo[2.2.2]-oct-3-yl)-4-phenyl-1H-pyrazol-3-yl]aminein 10 cm³ of dichloromethane, under argon and with stirring. Afterheating for 15 h at the reflux of the reaction medium, the mixture isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with 1N hydrochloric acid and the solution is washed with twotimes ethyl acetate. The resulting aqueous phase is alkylinized with 1Nsodium hydroxide and extracted with two times ethyl acetate. Thecombined organic phases are washed with a saturated aqueous sodiumchloride solution, dried over magnesium sulfate and evaporated underreduced pressure (2.7 kPa). The residue is taken up with dichloromethaneand the solution is treated with carbon black, filtered throughsupercel, and evaporated under reduced pressure (2.7 kPa), to give 130mg of(+/−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-ylamine inthe form of an orange oil. ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6(referenced at 2.50 ppm): from 1.20 to 1.38 (m, 1H); from 1.58 to 1.71(m, 3H); 2.07 (m, 1H); from 2.62 to 2.79 (m, 3H); from 2.88 to 3.63(partially masked m, 3H); 4.16 (m, 1H); 4.63 (broad s, 2H); 7.13 (broadt, J=7.5 Hz, 1H); 7.32 (broad t, J=7.5 Hz, 2H); 7.52 (broad d, J=7.5 Hz,2H); 7.89 (s, 1H).

Thediallyl-[1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-yl]aminecan be prepared in the following way:

A solution of 1.3 g of diallyl-(4-phenyl-1H-pyrazol-3-yl)amine and of730 mg of potassium tert-butoxide in 20 cm³ of dimethylformamide, underan argon atmosphere, is stirred for 45 min at 45° C. and then a solutionof 2.3 g of toluene-4-sulfonic acid 1-azabicyclo[2.2.2]-oct-3-yl esterin 15 cm³ of dimethylformamide is added thereto. After heating for 15 hat 100° C., the reaction medium is poured into water, and the mixture isextracted with two times ethyl acetate. The combined organic phases arewashed successively with two times water and a saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and evaporated underreduced pressure (2.7 kPa). The orange oil obtained (1.8 g) is purifiedby flash chromatography on alumina CTB1 under an argon pressure (50 kPa)[eluent: cyclohexane/ethyl acetate (60/40 by volume)]. Afterconcentrating the fractions under reduced pressure (2.7 kPa), an oil isobtained which is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: dichloromethane/methanol (50/50 byvolume)]. Concentrating the appropriate fractions under reduced pressure(2.7 kPa) gives 280 mg ofdiallyl-[1-(1-azabicyclo[2.2.2]oct-3-yl)-4-phenyl-1H-pyrazol-3-yl]aminecontaining 20% (estimated by ¹H NMR) ofdiallyl-(4-phenyl-1H-pyrazol-3-yl)amine in the form of a pale yellowoil. ¹H NMR spectrum (300 MHz)-δ in ppm-in DMSO-d6 (referenced at 2.50ppm): 1.29 (m, 1H); from 1.53 to 1.69 (m, 3H); 2.03 (m, 1H); from 2.62to 2.80 (m, 3H); 2.97 (m, 1H); 3.17 (m, 1H); 2.39 (m, 1H); from 3.52 to3.52 (m, 4H); 4.24 (m, 1H); from 4.98 to 5.17 (m, 4H); from 5.75 to 5.91(m, 2H); 7.17 (tt, J=1.5 and 7.5 Hz, 1H); 7.33 (broad t, J=7.5 Hz, 2H);7.61 (broad d, J=7.5 Hz, 2H); 7.93 (s, 1H).

The diallyl-(4-phenyl-1H-pyrazol-3-yl)amine can be prepared in thefollowing way:

22 cm³ of a 1N solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, under an argon atmosphere andwith stirring, of 2.9 g ofdiallyl-[4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-yl]aminein 25 cm³ of tetrahydrofuran. After heating to 18 h at the reflux of thesolvent, 6.3 cm³ of 1N tetrabutylammonium fluoride solution are addedand the heating is continued for 4 h. After evaporation of the reactionmedium to dryness under reduced pressure (2.7 kPa), ethyl acetate isadded to the residue and the organic phase is washed successively withtwo times water and a saturated aqueous sodium chloride solution; it isdried over magnesium sulfate and evaporated under reduced pressure (2.7kPa). The brown oil obtained (1.8 g) is purified by flash chromatographyon silica under an argon pressure (50 kPa) [eluent: cyclohexane/ethylacetate (70/30 by volume)]. After concentrating the fractions underreduced pressure (2.7 kPa), 1.3 g ofdiallyl-(4-phenyl-1H-pyrazol-3-yl)amine are obtained in the form of anorange oil. Mass spectrum (EI): m/z=239 (M^(+.)) base peak, m/z=198[(M-C₃H₅)⁺], m/z=41 (C₃H₅ ⁺)

Thediallyl-[4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-yl]aminecan be prepared in the following way:

8.17 g of cesium carbonate and 4.35 cm³ of allyl bromide are added to asolution, under an argon atmosphere and with stirring, of 2.9 g of4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-ylamine in 60cm³ of acetonitrile. After heating for 15 h at the reflux of thesolvent, the reaction medium is evaporated to dryness under reducedpressure (2.7 kPa) and the residue is taken up with ethyl acetate. Theorganic solution is washed successively with two times water and asaturated aqueous sodium chloride solution; it is dried over magnesiumsulfate and evaporated under reduced pressure (2.7 kPa). The orange oilobtained (4 g) is purified by flash chromatography on silica under anargon pressure (50 kPa) [eluent: cyclohexane/ethyl acetate (93/7 byvolume)]. After concentrating the fractions under reduced pressure (2.7kPa), 2.9 g ofdiallyl-[4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-yl]amineare obtained in the form of an orange oil. ¹H NMR spectrum (300 MHz)-δin ppm-in DMSO-d6 (referenced at 2.50 ppm): −0.03 (s, 9H); 0.83 (m, 2H);from 3.52 to 3.63 (m, 6H); from 5.04 to 5.15 (m, 4H); 5.24 (s, 2H); from5.74 to 5.90 (m, 2H); 7.21 (tt, J=1.5 and 7.5 Hz, 1H); 7.36 (broad t,J=7.5 Hz, 2H); 7.58 (broad d, J=7.5 Hz, 2H); 7.96 (s, 1H).

The 4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-ylamine canbe prepared in the following way:

3.7 g of iron, 1.8 g of ammonium chloride and then a solution of 3.5 gof 3-nitro-4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole in 50cm³ of ethanol are added to a mixture of 50 cm³ of ethanol and 50 cm³ ofwater. After heating for 8 h at the reflux of the solvent and withstirring, and for 15 h at a temperature in the region of 20° C., thereaction medium is filtered through supercel and the filtrate isevaporated to dryness under reduced pressure (2.7 kPa). The residue istaken up with ethyl acetate and the organic solution is washedsuccessively with two times water and a saturated aqueous sodiumchloride solution, and is then dried over magnesium sulfate andevaporated under reduced pressure (2.7 kPa), to give 2.9 g of4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-3-ylamine in theform of an orange oil. ¹H NMR spectrum (400 MHz)-δ in ppm-in DMSO-d6(referenced at 2.50 ppm): −0.01 (s, 9H); 0.86 (m, 2H); 3.56 (m, 2H);4.75 (broad s, 2H); 5.17 (s, 2H); 7.18 (broad t, J=7.5 Hz, 1H); 7.35(broad t, J=7.5 Hz, 2H); 7.50 (broad d, J=7.5 Hz, 2H); 7.88 (s, 1H).

The 3-nitro-4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole canbe prepared in the following way:

8.8 g of phenylboronic acid, 36 cm³ of a 2N aqueous potassium carbonatesolution and 3.6 g of tetrakis(triphenylphosphine)palladium are added toa solution, under an argon atmosphere and with stirring, of 7.8 g of4-iodo-3-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole in 120 cm³of toluene to which 30 cm³ of ethanol have been added. After heating for15 h at 100° C., the reaction medium is cooled to a temperature in theregion of 20° C. and is then evaporated under reduced pressure (2.7kPa). The residue is taken up with ethyl acetate and the organicsolution is washed successively with two times water and a saturatedaqueous sodium chloride solution; it is dried over magnesium sulfate andevaporated under reduced pressure (2.7 kPa), to give 14.3 g of a brownoil which is purified by flash chromatography on silica under an argonpressure (50 kPa) [eluent: cyclohexane/ethyl acetate (90/10 then 70/30by volume)]. Concentrating the appropriate fractions under reducedpressure (2.7 kPa) gives 4.5 g of3-nitro-4-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole in theform of a yellow oil. Mass spectrum (EI): m/z=319 (M^(+.)), m/z=246[(M-C₃H₉Si)⁺] base peak, m/z=73 (C₃H₉Si⁺).

The 4-iodo-3-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole can beprepared in the following way:

10 g of 3-nitro-4-phenyl-1H-pyrazole are added, portionwise, to asuspension of 1.7 g of sodium hydride (at 75% in liquid petroleum jelly)in 120 cm³ of dimethylformamide under an argon atmosphere and withstirring. The mixture is stirred for 45 min at a temperature in theregion of 20° C. and 14 cm³ of 2-trimethylsilanylethoxymethyl chlorideare then slowly added thereto. After stirring for 15 h at a temperaturein the region of 20° C., the reaction medium is poured into 500 cm² ofwater and the mixture is extracted with three times 500 cm³ of ethylacetate. The organic phases are combined, washed successively with twotimes water and a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated under reduced pressure (2.7kPa), to give an orange oil (22 g) which is purified by flashchromatography on silica under an argon pressure (50 kPa) [eluent:cyclohexane/ethyl acetate (85/15 by volume)]. After concentrating thefractions under reduced pressure, 7.8 g of4-iodo-3-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole areobtained in the form of a pale yellow oil. ¹H NMR spectrum (300 MHz)-δin ppm-in DMSO-d6 (referenced at 2.50 ppm): −0.03 (s, 9H); 0.87 (m, 2H);3.61 (m, 2H); 5.51 (s, 2H); 8.52 (s, 1H).

EXAMPLES 105 AND 1061-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolehydrochloride, Enantiomers A and B

The procedure is carried out as in example 38, but with 0.78 g of1-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-1H-pyrazole, 0.51 g of1H-indol-4-yl boronic acid pinacolic ester, 0.475 g of sodium carbonate,0.13 g of 1,1′-dichlorobis(diphenylphosphinoferrocene)palladium in 35cm³ of dioxane and 5 cm³ of water. After purification by chromatographyunder a nitrogen pressure of 50 kPa on a basic alumina cartridge(Merck), eluting with a mixture of cyclohexane and of ethyl acetate(50/50 then 25/75 then 10/90 by volume) and then with a mixture of ethylacetate and of methanol (95/5 by volume), fractions 49 to 120 arecombined, and concentrated to dryness under reduced pressure (3 kPa).Fractions 192 to 205 are combined, washed with 5 cm³ of water andconcentrated to dryness under reduced pressure (3 kPa). The 2 batches,in the form of an orange powder, are combined (266 mg) and purified byHPLC in order to separate the enantiomers on a 20 μm Chiralcel OD columnwith, as eluent, a mixture of heptane, of methanol, of ethanol and oftriethylamine (60/10/30/0.2 by volume); each enantiomer is then taken upwith 10 cm³ of dichloromethane and 5 cm³ of water. The organic phase iswashed with a saturated aqueous sodium chloride solution, dried overmagnesium sulfate, filtered, and concentrated to dryness under reducedpressure (3 kPa). Each white powder thus obtained is then taken up with20 cm³ of absolute ethanol and then brought to the reflux of the solventfor 20 minutes. Each solution is filtered and washed with 5 cm³ ofabsolute ethanol, and 1 cm³ of a 1N solution of hydrochloric diethylether is added thereto. The solutions are concentrated to dryness underreduced pressure, taken up with 5 cm³ of ethanol and again concentratedto dryness under reduced pressure; the residues are precipitated from 5cm³ of diisopropyl ether and then filtered through sintered glass. 45 mgof (+)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolehydrochloride, enantiomer A, in the form of a beige powder ([α]²⁰_(D)=+21.0°, solvent: dimethyl sulfoxide, concentration: 0.5) and 39 mgof (−)-1-(1-azabicyclo[2.2.2]oct-3-yl)-4-(1H-indol-4-yl)-1H-pyrazolehydrochloride, enantiomer B, in the form of a beige powder ([α]²⁰_(D)=−22.7°, solvent: dimethyl sulfoxide, concentration: 0.5) are thusobtained.

The pharmaceutical compositions according to the invention consist of acompound of formula (I) or a salt of such a compound, in the pure stateor in the form of a composition in which it is combined with any otherpharmaceutically compatible product, which may be inert orphysiologically active. The medicinal products according to theinvention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, use may be made oftablets, pills, powders (gelatin capsules, wafer capsules) or granules.In these compositions, the active principle according to the inventionis mixed with one or more inert diluents such as starch, cellulose,sucrose, lactose or silica, under a stream of argon. These compositionsmay also contain substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a dye, a coating(sugar-coated tablets) or a varnish.

As liquid compositions for oral administration, use may be made ofpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs, containing inert diluents such as water, ethanol, glycerol,plant oils or liquid paraffin. These compositions may comprisesubstances other than diluents, for example wetting, sweetening,thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration may preferably beaqueous or nonaqueous solutions, suspensions or emulsions. As a solventor vehicle, use may be made of water, propylene glycol, a polyethyleneglycol, plant oils, in particular olive oil, injectable organic esters,for example ethyl oleate, or other suitable organic solvents. Thesecompositions may also contain adjuvants, in particular wetting agents,tonicity agents, emulsifiers, dispersants and stabilizing agents. Thesterilization may be carried out in several ways, for example by asepticfiltration, by incorporating sterilizing agents into the composition, byirradiation or by heating. They may also be prepared in the form ofsterile solid compositions which can be dissolved at the time of use insterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, besides the active product, excipients such ascocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions for topical administration may, for example, be creams,lotions, eye washes, throat sprays, nasal drops or aerosols.

The doses depend on the desired effect, on the duration of the treatmentand on the route of administration used; they are generally between 5 mgand 1 000 mg per day orally for an adult, with single doses ranging from1 mg to 250 mg of active substance.

In general, the physician will determine the appropriate dosage inaccordance with the age, the weight and all the other factors specificto the individual to be treated.

The compounds of formula (I) according to the invention will be usefulas a medicinal product in the treatment of diseases due to a dysfunctionof alpha-7 nicotinic receptors or responding favorably to a modulationthereof; in the treatment, prevention, diagnosis and/or monitoring ofthe evolution of psychiatric disorders or diseases or neurologicaldisorders or diseases of the central nervous system involving animpairment of cognitive functions or of the processing of sensoryinformation.

More particularly, the diseases or the disorders treated concerncognitive abilities and attention capacity, the ability to concentrate,to learn and/or to memorize, Alzheimer's disease and related cognitivedisorders, senile dementia, vascular dementia, slight cognitiveimpairments, age-related amnesic deficits, cognitive impairments relatedto bacterial or viral infections, attention deficit hyperactivitydisorders, schizophrenia, the treatment of inflammatory syndromes,ulcerative colitis, Crohn's disease, irritable bowel syndrome,arthritis, the treatment of acute or chronic pain, fibromyalgia, thetreatment of acute neurone degeneration subsequent to a trauma, tostrokes, to ischemia or to brain hypoxia, the treatment of chronicneural degeneration observed during Parkinson's disease, Huntington'schorea, multisystem atrophy, progressive supranuclear paralysis oramyotrophic lateral sclerosis, the treatment of epilepsy, the treatmentof depression, of anxiety, of manic depressive psychoses, ofobsessive/compulsive disorders, of phobias, of post-traumatic stresssyndromes, of panic attacks, of Tourette's syndrome, of anorexia and ofbulimia, and sleep disorders.

The compounds of formula (I) can also be used for establishing adecrease in the consumption of addictive substances, for helping tomaintain an abstinence with respect to said substances or for reducingthe symptoms of withdrawal therefrom.

The compounds of formula (I) can also be used as a diagnostic agent.

The following examples illustrate compositions according to theinvention:

EXAMPLE A

Gelatin capsules containing a dose of 50 mg of active product, havingthe following composition, are prepared according to the conventionaltechnique:

Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mg Colloidalsilica  1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesiumstearate  1 mg

EXAMPLE B

Tablets containing a dose of 50 mg of active product, having thefollowing composition, are prepared according to the conventionaltechnique:

Compound of formula (I)  50 mg Lactose 104 mg Cellulose  40 mgPolyvidone  10 mg Sodium carboxymethylstarch  22 mg Talc  10 mgMagnesium stearate  2 mg Colloidal silica  2 mg Mixture ofhydroxymethylcellulose, glycerol, titanium oxide (72-3.5-24.5) qs 1film-coated tablet with a final weight of 245 mg

EXAMPLE C

An injectable solution containing 10 mg of active product, having thefollowing composition, is prepared:

Compound of formula (I) 10 mg Benzoic acid 80 mg Benzyl alcohol 0.06 mlSodium benzoate 80 mg 95% ethanol 0.4 ml Sodium hydroxide 24 mgPropylene glycol 1.6 ml water qs. 4 ml

1. A compound of formula (I) wherein

A is selected from the group consisting of (C1-C6) alkyl, (C3-C6)alkenyl and (C3-C6) alkynyl, optionally substituted with one or moresubstituents selected from the group consisting of (C1-C5) alkyl,(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,R1 is —NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9)azabicycloalkyl or (C5-C9) azabicycloalkenyl, optionally all of theaforementioned groups are substituted with one or more substituentsselected from the group consisting of (C1-C5) alkyl, (C3-C5) cycloalkyland halogen, A-R1 is such that the nitrogen of R1 and the nitrogen inthe 1-position of the pyrazole are necessarily separated by at least twocarbon atoms, R3 is H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra,NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra; R4 is aryl or heteroaryloptionally substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, NH₂, OH, SH, COOH, CHO, C(O)NH₂,C(S)NH₂, SO₂H, SO₂NH₂, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb,S(O)Ra, SO₂Ra, SO₂NRaRb, ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra,NHC(S)Ra, NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and(C2-C6) alkynyl, these substituents being optionally substituted withone or more substituents selected from the group consisting of alkyl,halogen, OH, and methoxy; R5 is H, halogen, CF₃, CHF₂, CH₂F, linear orbranched (C1-C6) alkyl or (C3-C7) cycloalkyl, Ra is linear or branched(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl or polyfluoroalkyl, Rb is, independently of Ra, ahydrogen, linear or branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) hetero cycloalkyl, arylalkyl,heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl, or Ra and Rb takentogether with the nitrogen atom to which they are attached form asaturated or unsaturated ring containing 5, 6 or 7 ring members,optionally containing one or more additional heteroatoms, wherein saidheteroatoms are O, S or N, and wherein said ring is optionallysubstituted with one or more alkyls and/or halogens, Rc is linear orbranched (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,heteroarylalkyl, heteroaryl, polyfluoroalkyl, C(O)R8, C(S)R8 or SO₂R8,R6 and R7 are, independently of one another, a hydrogen, (C1-C6) alkyl,(C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or heteroarylalkyl,or R6 and R7 taken together with the nitrogen atom to which they areattached form a saturated or unsaturated ring with 5, 6 or 7 ringmembers, optionally containing one or more additional heteroatoms,wherein said heteroatoms are O, S or N and and wherein said ring isoptionally substituted with one or more alkyls and/or halogens; and R8is Ra or NRaRb; or a racemate, an enantiomer or a diastereoisomer, or amixture in any combination thereof, a tautomer or a pharmaceuticallyacceptable salt thereof, with the exception of3-(3-pyridinyl)-1H-pyrazole-1-butanamine,4-(3-pyridinyl)-1H-pyrazole-1-butanamine andN-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.
 2. The compound of claim1 wherein A is selected from the group consisting of (C1-C6) alkyl,(C3-C6) alkenyl and (C3-C6) alkynyl, optionally substituted with one ormore substituents selected from the group consisting of (C1-C5) alkyl,(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,R1 is NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9)azabicycloalkyl or (C5-C9) azabicycloalkenyl, optionally all of theaforementioned groups are substituted with one or more substituentsselected from the group consisting of (C1-C5) alkyl, (C3-C5) cycloalkyland halogen, A-R1 is such that the nitrogen of R1 and the nitrogen inthe 1-position of the pyrazole are necessarily separated by at least twocarbon atoms, R3 is OH, NH₂, OCH₃ or H, R4 is aryl or heteroaryloptionally substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, NH₂, OH, SH, COOH, CHO, C(O)NH₂,C(S)NH₂, SO₂H, SO₂NH₂, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb,S(O)Ra, SO₂Ra, SO₂NRaRb, ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra,NHC(S)Ra, NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and(C2-C6) alkynyl, these substituents being optionally substituted withone or more alkyl, halogen, OH, or methoxy substituents, R5 is hydrogenor methyl, Ra is linear or branched (C1-C6) alkyl, alkenyl, alkynyl,(C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,arylalkyl, heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl, Rb is,independently of Ra, a hydrogen, linear or branched (C1-C6) alkyl,alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl orpolyfluoroalkyl, or Ra and Rb taken together with the nitrogen atom towhich they are attached form a saturated or unsaturated ring containing5, 6 or 7 ring members, optionally containing one or more additionalheteroatoms wherein said heteroatoms are O, S or N, and wherein saidring is optionally substituted with one or more alkyls and/or halogens,Rc is a linear or branched (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)heterocycloalkyl, heteroarylalkyl, heteroaryl, polyfluoroalkyl, C(O)R8,C(S)R8 or SO₂R8, R6 and R7 are, independently of one another, hydrogen,(C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl,(C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl orheteroarylalkyl, R6 and R7 taken together with the nitrogen atom towhich they are attached form a saturated or unsaturated ring with 5, 6or 7 ring members, optionally containing one or more additionalheteroatoms wherein said heteroatoms are O, S or N and and wherein saidring is optionally substituted with one or more alkyls and/or halogens;and R8 is an Ra or NRaRb, or a racemate, an enantiomer or adiastereoisomer, or a mixture in any combination thereof, a tautomer ora pharmaceutically acceptable salt thereof, with the exception of3-(3-pyridinyl)-1H-pyrazole-1-butanamine,4-(3-pyridinyl)-1H-pyrazole-1-butanamine andN-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.
 3. The compound of claim1 wherein A is selected from the group consisting of (C1-C6) alkyl,(C3-C6) alkenyl and (C3-C6) alkynyl, optionally substituted with one ormore substituents selected from the group consisting of (C1-C5) alkyl,(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,R1 is a NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9)azabicycloalkyl or (C5-C9) azabicycloalkenyl optionally substituted withone or more substituents selected from the group consisting of (C1-C5)alkyl, (C3-C5) cycloalkyl and halogen, A-R1 is such that the nitrogen ofR1 and the nitrogen in the 1-position of the pyrazole are necessarilyseparated by at least two carbon atoms, R3 is OH, NH₂, OCH₃ or H, R4 isan aryl or heteroaryl optionally substituted with one or moresubstituents selected from the group consisting of halogen, CN, NO₂,NH₂, OH, SH, COOH, CHO, C(O)NH₂, C(S)NH₂, SO₂H, SO₂NH₂, NHCHO, C(O)Ra,C(O)ORa, C(O)NRaRb, C(S)NRaRb, S(O)Ra, SO₂Ra, SO₂NRaRb, ORc, SRc,O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra, NHC(S)Ra, NHCONH₂, NHCONRaRb,NHSO₂Ra, aryl, heteroaryl, (C4-C7) heterocycloalkyl, polyfluoroalkyl,trifluoromethylsulfanyl, trifluoromethoxy, linear or branched (C1-C6)alkyl, (C2-C6) alkenyl and (C2-C6) alkynyl, these substituents beingoptionally substituted with one or more alkyl, halogen, OH, or methoxysubstituents, R5 is hydrogen, Ra is linear or branched (C1-C6) alkyl,alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl orpolyfluoroalkyl, Rb is, independently of Ra, a hydrogen, linear orbranched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl or polyfluoroalkyl, or Ra and Rb taken together withthe nitrogen atom to which they are attached form a saturated orunsaturated ring containing 5, 6 or 7 ring members, optionallycontaining one or more additional heteroatoms wherein said heteroatomsare O, S or N, and wherein said ring is optionally substituted with oneor more alkyls and/or halogens Rc is linear or branched (C1-C6) alkyl,(C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, heteroarylalkyl, heteroaryl,polyfluoroalkyl, C(O)R8, C(S)R8 or SO₂R8, R6 and R7 are, independentlyof one another, hydrogen, (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6)alkynyl, (C3-C7) cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7)heterocycloalkyl, arylalkyl or heteroarylalkyl, or R6 and R7 takentogether with the nitrogen atom to which they are attached form asaturated or unsaturated ring with 5, 6 or 7 ring members, optionallycontaining one or more additional heteroatoms wherein said heteroatomsare O, S or N and wherein said ring is optionally substituted with oneor more alkyls and/or halogens; and R8 is Ra or NRaRb or a racemate, anenantiomer or a diastereoisomer, or a mixture in any combinationthereof, a tautomer or a pharmaceutically acceptable salt thereof, withthe exception of 3-(3-pyridinyl)-1H-pyrazole-1-butanamine,4-(3-pyridinyl)-1H-pyrazole-1-butanamine andN-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine.
 4. The compound asclaimed in claim 1, selected from the group consisting of:1-[2-(3-Methoxy-4-phenylpyrazol-1-yl)ethyl]piperidine;1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol3-(3-Benzyloxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane;3-(3-Methoxy-4-phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]octane;1-(2-Perhydroazepin-1-ylethyl)-4-phenyl-1H-pyrazol-3-ol;1-[2-(2-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(4-Fluoropiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(3-Methylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(3,6-Dihydro-2H-pyridin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(7-Azabicyclo[2.2.1]hept-7-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(2-Azabicyclo[2.2.2]oct-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-(2-Azabicyclo[2.2.1]hept-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-Dimethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol;1-[3-Dimethylaminopropyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-((2S,6R)-2,6-Dimethylpiperidin-1-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-[2-Diethylaminoethyl]-4-phenyl-1H-pyrazol-3-ol;1-(2-Diisopropylaminoethyl)-4-phenyl-1H-pyrazol-3-ol;4-Phenyl-1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-3-ol;1-[2-(3-Difluoromethoxy-4-phenylpyrazol-1-yl)ethyl]-piperidine;4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine;4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ylamine;N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]acetamide;N-[4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-yl]methanesulfonamide;1-(1-Methylpiperidin-3-ylmethyl)-4-phenyl-1H-pyrazol-3-ol;5-Methyl-4-phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol;N-{3-[3-Hydroxy-1-(2-dimethylaminoethyl)-1H-pyrazol-4-yl]phenyl}acetamide;4-(4-Aminophenyl)-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol;1-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-3-yl)-1H-pyrazol-3-ol;4-Biphenyl-3-yl-1-(2-dimethylaminoethyl)-1H-pyrazol-3-ol;1-(2-Dimethylaminoethyl)-4-(4′-fluorobiphenyl-4-yl)-1H-pyrazol-3-ol;1-(2-Piperidin-1-ylethyl)-4-pyridin-2-yl-1H-pyrazol-3-ol;1-(2-Piperidin-1-ylethyl)-4-pyridin-4-yl-1H-pyrazol-3-ol;4-(4-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(4-Trifluoromethoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-Phenyl-1-(2-piperidin-1-ylpropyl)-1H-pyrazol-3-ol;3-(4-Phenylpyrazol-1-ylmethyl)-1-azabicyclo[2.2.2]-octane;4-(5-Chlorothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(2-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(4-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(4-Methoxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;1-(2-Piperidin-1-ylethyl)-4-(3-trifluoromethylphenyl)-1H-pyrazol-3-ol;1-(2-Piperidin-1-ylethyl)-4-pyridin-3-yl-1H-pyrazol-3-ol;4-(4-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(2-Fluorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(2-Chlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;1-[2-(1-Methylpyrrolidin-2-yl)ethyl]-4-phenyl-1H-pyrazol-3-ol;1-((2S)-1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol;1-((2R)-1-Methylpyrrolidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol;1-(1-Methylpiperidin-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol;4-Phenyl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(Thiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(3,4-Dichlorophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(4-Bromophenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;4-(5-Bromothiophen-2-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;2-[1-(2-Piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide;4-(2-Hydroxyphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole;4-(1H-Indol-5-yl)-1-(2-piperidin-1-ylethyl)-1H-pyrazole;4-(4-Methylphenyl)-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;1-(1-Azabicyclo[2.2.2]oct-2-ylmethyl)-4-phenyl-1H-pyrazol-3-ol;4-Benzo[b]thiophen-2-yl-1-(2-piperidin-1-ylethyl)-1H-pyrazol-3-ol;1-(2-Piperidin-1-ylethyl)-4-thiophen-3-yl-1H-pyrazol-3-ol;4-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide;3-[3-Hydroxy-1-(2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]benzamide;(−)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol;(+)-1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-phenyl-1H-pyrazol-1-ol;1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-4-(4-chlorophenyl)-1H-pyrazol-3-ol;3-[4-(4-Chlorophenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane;3-[4-(3-Chloro-4-methoxyphenyl)pyrazol-1-ylmethyl]-1-azabicyclo[2.2.2]octane;and4-[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]-2-chlorophenol;or a racemate, an enantiomer or a diastereoisomer or a mixture in anycombination thereof, a tautomer or a pharmaceutically acceptable saltthereof.
 5. A pharmaceutical composition, comprising a compound offormula I in a pharmaceutically acceptable medium wherein

A is selected from the group consisting of (C1-C6) alkyl, (C3-C6)alkenyl and (C3-C6) alkynyl, optionally substituted with one or moresubstituents selected from the group consisting of (C1-C5) alkyl,(C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl and halogen,R1 is —NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9)azabicycloalkyl or (C5-C9) azabicycloalkenyl, optionally all of theaforementioned groups are substituted with one or more substituentsselected from the group consisting of (C1-C5) alkyl, (C3-C5) cycloalkyland halogen, A-R1 is such that the nitrogen of R1 and the nitrogen inthe 1-position of the pyrazole are necessarily separated by at least twocarbon atoms, R3 is H, halogen, OH, SH, NH₂, ORc, SRc, SORa, SO₂Ra,NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO₂Ra, R4 is an aryl or heteroaryloptionally substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, NH₂, OH, SH, COOH, CHO, C(O)NH₂,C(S)NH₂, SO₂H, SO₂NH₂, NHCHO, C(O)Ra, C(O)ORa, C(O)NRaRb, C(S)NRaRb,S(O)Ra, SO₂Ra, SO₂NRaRb, ORc, SRc, O—C(O)Ra, —O—C(S)Ra, NRaRb, NHC(O)Ra,NHC(S)Ra, NHCONH₂, NHCONRaRb, NHSO₂Ra, aryl, heteroaryl, (C4-C7)heterocycloalkyl, polyfluoroalkyl, trifluoromethylsulfanyl,trifluoromethoxy, linear or branched (C1-C6) alkyl, (C2-C6) alkenyl and(C2-C6) alkynyl, these substituents being optionally substituted withone or more substituents selected from the group consisting of alkyl,halogen, OH, and methoxy, R5 is H, halogen, CF₃, CHF₂, CH₂F, linear orbranched (C1-C6) alkyl or (C3-C7) cycloalkyl, Ra is linear or branched(C1-C6) alkyl, alkenyl, alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl or polyfluoroalkyl, Rb is, independently of Ra, ahydrogen, linear or branched (C1-C6) alkyl, alkenyl, alkynyl, (C3-C7)cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl, arylalkyl,heteroarylalkyl, aryl, heteroaryl or polyfluoroalkyl, or Ra and Rb takentogether with the nitrogen atom to which they are attached form asaturated or unsaturated ring containing 5, 6 or 7 ring members,optionally containing one or more additional heteroatoms, wherein saidheteroatoms are O, S or N, and wherein said ring is optionallysubstituted with one or more alkyls and/or halogens, Rc is linear orbranched (C1-C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7)cycloalkyl, (C5-C7) cycloalkenyl, (C4-C7) heterocycloalkyl,heteroarylalkyl, heteroaryl, polyfluoroalkyl, C(O)R8, C(S)R8 or SO₂R8,R6 and R7 are, independently of one another, a hydrogen, (C1-C6) alkyl,(C3-C6) alkenyl, (C3-C6) alkynyl, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C4-C7) heterocycloalkyl, an arylalkyl or heteroarylalkyl,or R6 and R7 taken together with the nitrogen atom to which they areattached form a saturated or unsaturated ring with 5, 6 or 7 ringmembers, optionally containing one or more additional heteroatoms,wherein said heteroatoms are O, S or N and and wherein said ring isoptionally substituted with one or more alkyls and/or halogens; and R8is Ra or NRaRb or a racemate, an enantiomer or a diastereoisomer, or amixture in any combination thereof, a tautomer or a pharmaceuticallyacceptable salt thereof.
 6. A process for preparing the compounds offormula (I) as defined in claim 1, wherein R3 is OH from compound offormula (II)

wherein GP is a hydroxyl function-protecting group, comprising removingthe hydroxyl function-protecting group and optionally converting theproduct into a pharmaceutically acceptable salt.
 7. A process forpreparing the compounds of formula (I) as defined in claim 1, wherein R3is ORc, H or NH₂, comprising the steps of: 1.) alkylating a pyrazole offormula (III)

wherein GP is an OH function-protecting group, with a compound offormula (IV) R1-A-X wherein X is Cl, Br, I, OTs, OMs or OTf, in basicmedium in an aprotic solvent, 2.) optionally removing the OHfunction-protecting group from the product of step 1; and 3.) optionallyforming a pharmaceutically acceptable salt.